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The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease

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Abstract

The Tousled-like kinases (TLKs) are an evolutionarily conserved family of serine–threonine kinases that have been implicated in DNA replication, DNA repair, transcription, chromatin structure, viral latency, cell cycle checkpoint control and chromosomal stability in various organisms. The functions of the TLKs appear to depend largely on their ability to regulate the H3/H4 histone chaperone ASF1, although numerous TLK substrates have been proposed. Over the last few years, a clearer picture of TLK function has emerged through the identification of new partners, the definition of specific roles in development and the elucidation of their structural and biochemical properties. In addition, the TLKs have been clearly linked to human disease; both TLK1 and TLK2 are frequently amplified in human cancers and TLK2 mutations have been identified in patients with neurodevelopmental disorders characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. A better understanding of the substrates, regulation and diverse roles of the TLKs is needed to understand their functions in neurodevelopment and determine if they are viable targets for cancer therapy. In this review, we will summarize current knowledge of TLK biology and its potential implications in development and disease.

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References

  1. Roe JL, Rivin CJ, Sessions RA, Feldmann KA, Zambryski PC (1993) The Tousled gene in A. thaliana encodes a protein kinase homolog that is required for leaf and flower development. Cell 75(5):939–950. https://doi.org/10.1016/0092-8674(93)90537-Z

    Article  CAS  PubMed  Google Scholar 

  2. Ehsan H, Reichheld JP, Durfee T, Roe JL (2004) TOUSLED kinase activity oscillates during the cell cycle and interacts with chromatin regulators. Plant Physiol 134(4):1488–1499. https://doi.org/10.1104/pp.103.038117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang Y, Liu J, Xia R, Wang J, Shen J, Cao R, Hong X, Zhu JK, Gong Z (2007) The protein kinase TOUSLED is required for maintenance of transcriptional gene silencing in Arabidopsis. EMBO Rep 8(1):77–83. https://doi.org/10.1038/sj.embor.7400852

    Article  CAS  PubMed  Google Scholar 

  4. Uddin MN, Dunoyer P, Schott G, Akhter S, Shi C, Lucas WJ, Voinnet O, Kim JY (2014) The protein kinase TOUSLED facilitates RNAi in Arabidopsis. Nucleic Acids Res 42(12):7971–7980. https://doi.org/10.1093/nar/gku422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Han Z, Saam JR, Adams HP, Mango SE, Schumacher JM (2003) The C. elegans Tousled-like kinase (TLK-1) has an essential role in transcription. Curr Biol 13(22):1921–1929. https://doi.org/10.1016/j.cub.2003.10.035

    Article  CAS  PubMed  Google Scholar 

  6. Han Z, Riefler GM, Saam JR, Mango SE, Schumacher JM (2005) The C. elegans Tousled-like kinase contributes to chromosome segregation as a substrate and regulator of the Aurora B kinase. Curr Biol 15(10):894–904. https://doi.org/10.1016/j.cub.2003.10.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carrera P, Moshkin YM, Gronke S, Sillje HH, Nigg EA, Jackle H, Karch F (2003) Tousled-like kinase functions with the chromatin assembly pathway regulating nuclear divisions. Genes Dev 17(20):2578–2590. https://doi.org/10.1101/gad.276703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Z, Gourguechon S, Wang CC (2007) Tousled-like kinase in a microbial eukaryote regulates spindle assembly and S-phase progression by interacting with Aurora kinase and chromatin assembly factors. J Cell Sci 120(Pt 21):3883–3894. https://doi.org/10.1242/jcs.007955

    Article  CAS  PubMed  Google Scholar 

  9. Sillje HH, Nigg EA (2001) Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Curr Biol 11(13):1068–1073. https://doi.org/10.1016/S0960-9822(01)00298-6

    Article  CAS  PubMed  Google Scholar 

  10. Klimovskaia IM, Young C, Stromme CB, Menard P, Jasencakova Z, Mejlvang J, Ask K, Ploug M, Nielsen ML, Jensen ON, Groth A (2014) Tousled-like kinases phosphorylate Asf1 to promote histone supply during DNA replication. Nat Commun 5:3394. https://doi.org/10.1038/ncomms4394

    Article  CAS  PubMed  Google Scholar 

  11. Xiang W, Zhang D, Montell DJ (2016) Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration. Mol Biol Cell 27(1):12–19. https://doi.org/10.1091/mbc.E15-05-0327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sillje HH, Takahashi K, Tanaka K, Van Houwe G, Nigg EA (1999) Mammalian homologues of the plant Tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication. EMBO J 18(20):5691–5702. https://doi.org/10.1093/emboj/18.20.5691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li Y, DeFatta R, Anthony C, Sunavala G, De Benedetti A (2001) A translationally regulated Tousled kinase phosphorylates histone H3 and confers radioresistance when overexpressed. Oncogene 20(6):726–738. https://doi.org/10.1038/sj.onc.1204147

    Article  CAS  PubMed  Google Scholar 

  14. Shalom S, Don J (1999) Tlk, a novel evolutionarily conserved murine serine threonine kinase, encodes multiple testis transcripts. Mol Reprod Dev 52(4):392–405. https://doi.org/10.1002/(SICI)1098-2795(199904)52:4%3c392:AID-MRD8%3e3.0.CO;2-Y

    Article  CAS  PubMed  Google Scholar 

  15. Yamakawa A, Kameoka Y, Hashimoto K, Yoshitake Y, Nishikawa K, Tanihara K, Date T (1997) cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal. Gene 202(1–2):193–201

    Article  CAS  PubMed  Google Scholar 

  16. Zhang S, Xing H, Muslin AJ (1999) Nuclear localization of protein kinase U-alpha is regulated by 14-3-3. J Biol Chem 274(35):24865–24872

    Article  CAS  PubMed  Google Scholar 

  17. Sunavala-Dossabhoy G, Fowler M, De Benedetti A (2004) Translation of the radioresistance kinase TLK1B is induced by gamma-irradiation through activation of mTOR and phosphorylation of 4E-BP1. BMC Mol Biol 5:1. https://doi.org/10.1186/1471-2199-5-1

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sunavala-Dossabhoy G (2018) Preserving salivary gland physiology against genotoxic damage—the Tousled way. Oral Dis 24(8):1390–1398. https://doi.org/10.1111/odi.12836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Groth A, Lukas J, Nigg EA, Sillje HH, Wernstedt C, Bartek J, Hansen K (2003) Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J 22(7):1676–1687. https://doi.org/10.1093/emboj/cdg151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Krause DR, Jonnalagadda JC, Gatei MH, Sillje HH, Zhou BB, Nigg EA, Khanna K (2003) Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene 22(38):5927–5937. https://doi.org/10.1038/sj.onc.1206691

    Article  CAS  PubMed  Google Scholar 

  21. Mortuza GB, Hermida D, Pedersen AK, Segura-Bayona S, López-Méndez B, Redondo P, Garrote AM, Muñoz IG, Villamor-Paya M, Jauset C, Olsen JV, Stracker TH, Montoya G (2018) Molecular basis of Tousled Like kinase 2 activation. Nat Commun 9(1):2535. https://doi.org/10.1038/s41467-018-04941-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leroux AE, Schulze JO, Biondi RM (2018) AGC kinases, mechanisms of regulation and innovative drug development. Semin Cancer Biol 48:1–17. https://doi.org/10.1016/j.semcancer.2017.05.011

    Article  CAS  PubMed  Google Scholar 

  23. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res 43:512–520. https://doi.org/10.1093/nar/gku1267

    Article  CAS  Google Scholar 

  24. Kosugi S, Hasebe M, Tomita M, Yanagawa H (2009) Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Proc Natl Acad Sci USA 106(25):10171–10176. https://doi.org/10.1073/pnas.0900604106

    Article  PubMed  PubMed Central  Google Scholar 

  25. Huang TH, Fowler F, Chen CC, Shen ZJ, Sleckman B, Tyler JK (2018) The histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL-mediated Rad51 loading onto ssDNA during homologous recombination in human cells. Mol Cell 69(5):879–892. https://doi.org/10.1016/j.molcel.2018.01.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pilyugin M, Demmers J, Verrijzer CP, Karch F, Moshkin YM (2009) Phosphorylation-mediated control of histone chaperone ASF1 levels by Tousled-like kinases. PLoS One 4(12):e8328. https://doi.org/10.1371/journal.pone.0008328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hammond CM, Stromme CB, Huang H, Patel DJ, Groth A (2017) Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol 18(3):141–158. https://doi.org/10.1038/nrm.2016.159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee SB, Segura-Bayona S, Villamor-Paya M, Saredi G, Todd MAM, Attolini CS, Chang TY, Stracker TH, Groth A (2018) Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Sci Adv. https://doi.org/10.1126/sciadv.aat4985

    Article  PubMed  PubMed Central  Google Scholar 

  29. Singh V, Connelly ZM, Shen X, De Benedetti A (2017) Identification of the proteome complement of humanTLK1 reveals it binds and phosphorylates NEK1 regulating its activity. Cell Cycle 78:89. https://doi.org/10.1080/15384101.2017.1314421

    Article  CAS  Google Scholar 

  30. Kelly R, Davey SK (2013) Tousled-like kinase-dependent phosphorylation of Rad9 plays a role in cell cycle progression and G2/M checkpoint exit. PLoS One 8(12):e85859. https://doi.org/10.1371/journal.pone.0085859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM (2007) The Rad9–Hus1–Rad1 (9–1–1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21(12):1472–1477. https://doi.org/10.1101/gad.1547007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Canfield C, Rains J, De Benedetti A (2009) TLK1B promotes repair of DSBs via its interaction with Rad9 and Asf1. BMC Mol Biol 10:110. https://doi.org/10.1186/1471-2199-10-110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sunavala-Dossabhoy G, De Benedetti A (2009) Tousled homolog, TLK1, binds and phosphorylates Rad9; TLK1 acts as a molecular chaperone in DNA repair. DNA Repair (Amst) 8(1):87–102. https://doi.org/10.1016/j.dnarep.2008.09.005

    Article  CAS  Google Scholar 

  34. Lieberman HB (2006) Rad9, an evolutionarily conserved gene with multiple functions for preserving genomic integrity. J Cell Biochem 97(4):690–697. https://doi.org/10.1002/jcb.20759

    Article  CAS  PubMed  Google Scholar 

  35. Awate S, De Benedetti A (2016) TLK1B mediated phosphorylation of Rad9 regulates its nuclear/cytoplasmic localization and cell cycle checkpoint. BMC Mol Biol 17:3. https://doi.org/10.1186/s12867-016-0056-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Segura-Bayona S, Knobel PA, Gonzalez-Buron H, Youssef SA, Pena-Blanco A, Coyaud E, Lopez-Rovira T, Rein K, Palenzuela L, Colombelli J, Forrow S, Raught B, Groth A, de Bruin A, Stracker TH (2017) Differential requirements for Tousled-like kinases 1 and 2 in mammalian development. Cell Death Differ. https://doi.org/10.1038/cdd.2017.108

    Article  PubMed  PubMed Central  Google Scholar 

  37. Crosio C, Fimia GM, Loury R, Kimura M, Okano Y, Zhou H, Sen S, Allis CD, Sassone-Corsi P (2002) Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 22(3):874–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fry AM, Bayliss R, Roig J (2017) Mitotic regulation by NEK kinase networks. Front Cell Dev Biol 5:102. https://doi.org/10.3389/fcell.2017.00102

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kenna KP, van Doormaal PT, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, van Rheenen W, van Eijk KR, Jones AR, Keagle P, Shatunov A, Sproviero W, Smith BN, van Es MA, Topp SD, Kenna A, Miller JW, Fallini C, Tiloca C, McLaughlin RL, Vance C, Troakes C, Colombrita C, Mora G, Calvo A, Verde F, Al-Sarraj S, King A, Calini D, de Belleroche J, Baas F, van der Kooi AJ, de Visser M, Ten Asbroek AL, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Munoz-Blanco JL, Strom TM, Meitinger T, Morrison KE, Consortium S, Lauria G, Williams KL, Leigh PN, Nicholson GA, Blair IP, Leblond CS, Dion PA, Rouleau GA, Pall H, Shaw PJ, Turner MR, Talbot K, Taroni F, Boylan KB, Van Blitterswijk M, Rademakers R, Esteban-Perez J, Garcia-Redondo A, Van Damme P, Robberecht W, Chio A, Gellera C, Drepper C, Sendtner M, Ratti A, Glass JD, Mora JS, Basak NA, Hardiman O, Ludolph AC, Andersen PM, Weishaupt JH, Jr Brown RH, Al-Chalabi A, Silani V, Shaw CE, van den Berg LH, Veldink JH, Landers JE (2016) NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet 48(9):1037–1042. https://doi.org/10.1038/ng.3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu S, Ho CK, Ouyang J, Zou L (2013) Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling. Proc Natl Acad Sci USA 110(6):2175–2180. https://doi.org/10.1073/pnas.1217781110

    Article  PubMed  PubMed Central  Google Scholar 

  41. Rapali P, Szenes A, Radnai L, Bakos A, Pal G, Nyitray L (2011) DYNLL/LC8: a light chain subunit of the dynein motor complex and beyond. FEBS J 278(17):2980–2996. https://doi.org/10.1111/j.1742-4658.2011.08254.x

    Article  CAS  PubMed  Google Scholar 

  42. Hutchins JR, Toyoda Y, Hegemann B, Poser I, Heriche JK, Sykora MM, Augsburg M, Hudecz O, Buschhorn BA, Bulkescher J, Conrad C, Comartin D, Schleiffer A, Sarov M, Pozniakovsky A, Slabicki MM, Schloissnig S, Steinmacher I, Leuschner M, Ssykor A, Lawo S, Pelletier L, Stark H, Nasmyth K, Ellenberg J, Durbin R, Buchholz F, Mechtler K, Hyman AA, Peters JM (2010) Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science 328(5978):593–599. https://doi.org/10.1126/science.1181348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, Gak IA, Weisswange I, Mansfeld J, Buchholz F, Hyman AA, Mann M (2015) A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 163(3):712–723. https://doi.org/10.1016/j.cell.2015.09.053

    Article  CAS  PubMed  Google Scholar 

  44. Rapali P, Garcia-Mayoral MF, Martinez-Moreno M, Tarnok K, Schlett K, Albar JP, Bruix M, Nyitray L, Rodriguez-Crespo I (2011) LC8 dynein light chain (DYNLL1) binds to the C-terminal domain of ATM-interacting protein (ATMIN/ASCIZ) and regulates its subcellular localization. Biochem Biophys Res Commun 414(3):493–498. https://doi.org/10.1016/j.bbrc.2011.09.093

    Article  CAS  PubMed  Google Scholar 

  45. Lo KW, Kan HM, Chan LN, Xu WG, Wang KP, Wu Z, Sheng M, Zhang M (2005) The 8-kDa dynein light chain binds to p53-binding protein 1 and mediates DNA damage-induced p53 nuclear accumulation. J Biol Chem 280(9):8172–8179. https://doi.org/10.1074/jbc.M411408200

    Article  CAS  PubMed  Google Scholar 

  46. He YJ, Meghani K, Caron MC, Yang C, Ronato DA, Bian J, Sharma A, Moore J, Niraj J, Detappe A, Doench JG, Legube G, Root DE, D’Andrea AD, Drane P, De S, Konstantinopoulos PA, Masson JY, Chowdhury D (2018) DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563(7732):522–526. https://doi.org/10.1038/s41586-018-0670-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Becker JR, Cuella-Martin R, Barazas M, Liu R, Oliveira C, Oliver AW, Bilham K, Holt AB, Blackford AN, Heierhorst J, Jonkers J, Rottenberg S, Chapman JR (2018) The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat Commun 9(1):5406. https://doi.org/10.1038/s41467-018-07855-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Regue L, Sdelci S, Bertran MT, Caelles C, Reverter D, Roig J (2011) DYNLL/LC8 protein controls signal transduction through the Nek9/Nek6 signaling module by regulating Nek6 binding to Nek9. J Biol Chem 286(20):18118–18129. https://doi.org/10.1074/jbc.M110.209080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shi T, Bunker RD, Mattarocci S, Ribeyre C, Faty M, Gut H, Scrima A, Rass U, Rubin SM, Shore D, Thoma NH (2013) Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. Cell 153(6):1340–1353. https://doi.org/10.1016/j.cell.2013.05.007

    Article  CAS  PubMed  Google Scholar 

  50. Mattarocci S, Hafner L, Lezaja A, Shyian M, Shore D (2016) Rif1: a conserved regulator of DNA replication and repair hijacked by telomeres in yeasts. Front Genet 7:45. https://doi.org/10.3389/fgene.2016.00045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Buonomo SBC (2017) Rif1-dependent regulation of genome replication in mammals. Adv Exp Med Biol 1042:259–272. https://doi.org/10.1007/978-981-10-6955-0_12

    Article  CAS  PubMed  Google Scholar 

  52. Silverman J, Takai H, Buonomo SB, Eisenhaber F, de Lange T (2004) Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev 18(17):2108–2119. https://doi.org/10.1101/gad.1216004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang S, Liu L, Cao C, Song N, Wang Y, Ma S, Zhang Q, Yu N, Ding X, Yang F, Tian S, Zhang K, Sun T, Yang J, Yao Z, Wu S, Shi L (2018) USP52 acts as a deubiquitinase and promotes histone chaperone ASF1A stabilization. Nat Commun 9(1):1285. https://doi.org/10.1038/s41467-018-03588-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sukackaite R, Cornacchia D, Jensen MR, Mas PJ, Blackledge M, Enervald E, Duan G, Auchynnikava T, Kohn M, Hart DJ, Buonomo SBC (2017) Mouse Rif1 is a regulatory subunit of protein phosphatase 1 (PP1). Sci Rep 7(1):2119. https://doi.org/10.1038/s41598-017-01910-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Srivastava M, Chen Z, Zhang H, Tang M, Wang C, Jung SY, Chen J (2018) Replisome dynamics and their functional relevance upon DNA damage through the PCNA interactome. Cell Rep 25(13):3869–3883. https://doi.org/10.1016/j.celrep.2018.11.099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M, Typas D, Lammers M, Mailand N, Nussenzweig A, Lukas J, Choudhary C (2018) DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell 173(4):972–988. https://doi.org/10.1016/j.cell.2018.03.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee KY, Im JS, Shibata E, Dutta A (2017) ASF1a promotes non-homologous end joining repair by facilitating phosphorylation of MDC1 by ATM at double-strand breaks. Mol Cell 68(1):61–75. https://doi.org/10.1016/j.molcel.2017.08.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Roe JL, Durfee T, Zupan JR, Repetti PP, McLean BG, Zambryski PC (1997) TOUSLED is a nuclear serine/threonine protein kinase that requires a coiled-coil region for oligomerization and catalytic activity. J Biol Chem 272(9):5838–5845

    Article  CAS  PubMed  Google Scholar 

  59. Hartford SA, Luo Y, Southard TL, Min IM, Lis JT, Schimenti JC (2011) Minichromosome maintenance helicase paralog MCM9 is dispensible for DNA replication but functions in germ-line stem cells and tumor suppression. Proc Natl Acad Sci USA 108(43):17702–17707. https://doi.org/10.1073/pnas.1113524108

    Article  PubMed  PubMed Central  Google Scholar 

  60. Lai M, Liang L, Chen J, Qiu N, Ge S, Ji S, Shi T, Zhen B, Liu M, Ding C, Wang Y, Qin J (2016) Multidimensional proteomics reveals a role of UHRF2 in the regulation of epithelial–mesenchymal transition (EMT). Mol Cell Proteom 15(7):2263–2278. https://doi.org/10.1074/mcp.M115.057448

    Article  CAS  Google Scholar 

  61. Wang J, Huo K, Ma L, Tang L, Li D, Huang X, Yuan Y, Li C, Wang W, Guan W, Chen H, Jin C, Wei J, Zhang W, Yang Y, Liu Q, Zhou Y, Zhang C, Wu Z, Xu W, Zhang Y, Liu T, Yu D, Zhang Y, Chen L, Zhu D, Zhong X, Kang L, Gan X, Yu X, Ma Q, Yan J, Zhou L, Liu Z, Zhu Y, Zhou T, He F, Yang X (2011) Toward an understanding of the protein interaction network of the human liver. Mol Syst Biol 7:536. https://doi.org/10.1038/msb.2011.67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Correia SP, Chan AB, Vaughan M, Zolboot N, Perea V, Huber AL, Kriebs A, Moresco JJ, Yates JR 3rd, Lamia KA (2019) The circadian E3 ligase complex SCF(FBXL3 + CRY) targets TLK2. Sci Rep 9(1):198. https://doi.org/10.1038/s41598-018-36618-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu H, Dowdle JA, Khurshid S, Sullivan NJ, Bertos N, Rambani K, Mair M, Daniel P, Wheeler E, Tang X, Toth K, Lause M, Harrigan ME, Eiring K, Sullivan C, Sullivan MJ, Chang SW, Srivastava S, Conway JS, Kladney R, McElroy J, Bae S, Lu Y, Tofigh A, Saleh SMI, Fernandez SA, Parvin JD, Coppola V, Macrae ER, Majumder S, Shapiro CL, Yee LD, Ramaswamy B, Hallett M, Ostrowski MC, Park M, Chamberlin HM, Leone G (2017) Discovery of stromal regulatory networks that suppress Ras-sensitized epithelial cell proliferation. Dev Cell 41(4):392–407. https://doi.org/10.1016/j.devcel.2017.04.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Emili A, Schieltz DM, Yates JR 3rd, Hartwell LH (2001) Dynamic interaction of DNA damage checkpoint protein Rad53 with chromatin assembly factor Asf1. Mol Cell 7(1):13–20

    Article  CAS  PubMed  Google Scholar 

  65. Hu F, Alcasabas AA, Elledge SJ (2001) Asf1 links Rad53 to control of chromatin assembly. Genes Dev 15(9):1061–1066. https://doi.org/10.1101/gad.873201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Blasius M, Forment JV, Thakkar N, Wagner SA, Choudhary C, Jackson SP (2011) A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1. Genome Biol 12(8):R78. https://doi.org/10.1186/gb-2011-12-8-r78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bruinsma W, van den Berg J, Aprelia M, Medema RH (2016) Tousled-like kinase 2 regulates recovery from a DNA damage-induced G2 arrest. EMBO Rep 17(5):659–670. https://doi.org/10.15252/embr.201540767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kim JA, Anurag M, Veeraraghavan J, Schiff R, Li K, Wang X (2016) Amplification of TLK2 induces genomic instability via impairing the G2/M checkpoint. Mol Cancer Res 78:89. https://doi.org/10.1158/1541-7786.mcr-16-0161

    Article  Google Scholar 

  69. Liaw GJ, Chiang CS (2019) Inactive Tlk associating with Tak1 increases p38 MAPK activity to prolong the G2 phase. Sci Rep 9(1):1885. https://doi.org/10.1038/s41598-018-36137-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sunavala-Dossabhoy G, Li Y, Williams B, De Benedetti A (2003) A dominant negative mutant of TLK1 causes chromosome missegregation and aneuploidy in normal breast epithelial cells. BMC Cell Biol 4:16. https://doi.org/10.1186/1471-2121-4-16

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hashimoto M, Matsui T, Iwabuchi K, Date T (2008) PKU-beta/TLK1 regulates myosin II activities, and is required for accurate equaled chromosome segregation. Mutat Res 657(1):63–67. https://doi.org/10.1016/j.mrgentox.2008.09.001

    Article  CAS  PubMed  Google Scholar 

  72. Gaillard H, Garcia-Muse T, Aguilera A (2015) Replication stress and cancer. Nat Rev Cancer 15(5):276–289. https://doi.org/10.1038/nrc3916

    Article  CAS  PubMed  Google Scholar 

  73. Saredi G, Huang H, Hammond CM, Alabert C, Bekker-Jensen S, Forne I, Reveron-Gomez N, Foster BM, Mlejnkova L, Bartke T, Cejka P, Mailand N, Imhof A, Patel DJ, Groth A (2016) H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex. Nature 534(7609):714–718. https://doi.org/10.1038/nature18312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, Bekker-Jensen S, Mailand N, Bartek J, Lukas J (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155(5):1088–1103. https://doi.org/10.1016/j.cell.2013.10.043

    Article  CAS  PubMed  Google Scholar 

  75. Chapman JR, Taylor MR, Boulton SJ (2012) Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 47(4):497–510. https://doi.org/10.1016/j.molcel.2012.07.029

    Article  CAS  PubMed  Google Scholar 

  76. Groth A, Corpet A, Cook AJ, Roche D, Bartek J, Lukas J, Almouzni G (2007) Regulation of replication fork progression through histone supply and demand. Science 318(5858):1928–1931. https://doi.org/10.1126/science.1148992

    Article  CAS  PubMed  Google Scholar 

  77. Huang H, Stromme CB, Saredi G, Hodl M, Strandsby A, Gonzalez-Aguilera C, Chen S, Groth A, Patel DJ (2015) A unique binding mode enables MCM2 to chaperone histones H3–H4 at replication forks. Nat Struct Mol Biol 22(8):618–626. https://doi.org/10.1038/nsmb.3055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dillon PJ, Gregory SM, Tamburro K, Sanders MK, Johnson GL, Raab-Traub N, Dittmer DP, Damania B (2013) Tousled-like kinases modulate reactivation of gammaherpesviruses from latency. Cell Host Microbe 13(2):204–214. https://doi.org/10.1016/j.chom.2012.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. O’Sullivan RJ, Arnoult N, Lackner DH, Oganesian L, Haggblom C, Corpet A, Almouzni G, Karlseder J (2014) Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1. Nat Struct Mol Biol 21(2):167–174. https://doi.org/10.1038/nsmb.2754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Houlard M, Berlivet S, Probst AV, Quivy JP, Hery P, Almouzni G, Gerard M (2006) CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells. PLoS Genet 2(11):e181. https://doi.org/10.1371/journal.pgen.0020181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Udugama M, Chang FT, Chan FL, Tang MC, Pickett HA, McGhie RJD, Mayne L, Collas P, Mann JR, Wong LH (2015) Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. Nucleic Acids Res 43(21):10227–10237. https://doi.org/10.1093/nar/gkv847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Elsasser SJ, Noh KM, Diaz N, Allis CD, Banaszynski LA (2015) Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522(7555):240–244. https://doi.org/10.1038/nature14345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Banaszynski LA, Wen D, Dewell S, Whitcomb SJ, Lin M, Diaz N, Elsasser SJ, Chapgier A, Goldberg AD, Canaani E, Rafii S, Zheng D, Allis CD (2013) Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. Cell 155(1):107–120. https://doi.org/10.1016/j.cell.2013.08.061

    Article  CAS  PubMed  Google Scholar 

  84. Segura-Bayona S, Villamor-Paya M, Attolini CS, Stracker TH (2019) Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling. bioRxiv. https://doi.org/10.1101/621409

    Article  Google Scholar 

  85. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1. https://doi.org/10.1126/scisignal.2004088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

    Article  PubMed  Google Scholar 

  87. Lecona E, Fernandez-Capetillo O (2018) Targeting ATR in cancer. Nat Rev Cancer 18(9):586–595. https://doi.org/10.1038/s41568-018-0034-3

    Article  CAS  PubMed  Google Scholar 

  88. Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Lohner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C (2016) Meta-analysis of 2104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci 19(9):1194–1196. https://doi.org/10.1038/nn.4352

    Article  CAS  PubMed  Google Scholar 

  89. Reijnders MRF, Miller KA, Alvi M, Goos JAC, Lees MM, de Burca A, Henderson A, Kraus A, Mikat B, de Vries BBA, Isidor B, Kerr B, Marcelis C, Schluth-Bolard C, Deshpande C, Ruivenkamp CAL, Wieczorek D, Deciphering Developmental Disorders S, Baralle D, Blair EM, Engels H, Ludecke HJ, Eason J, Santen GWE, Clayton-Smith J, Chandler K, Tatton-Brown K, Payne K, Helbig K, Radtke K, Nugent KM, Cremer K, Strom TM, Bird LM, Sinnema M, Bitner-Glindzicz M, van Dooren MF, Alders M, Koopmans M, Brick L, Kozenko M, Harline ML, Klaassens M, Steinraths M, Cooper NS, Edery P, Yap P, Terhal PA, van der Spek PJ, Lakeman P, Taylor RL, Littlejohn RO, Pfundt R, Mercimek-Andrews S, Stegmann APA, Kant SG, McLean S, Joss S, Swagemakers SMA, Douzgou S, Wall SA, Kury S, Calpena E, Koelling N, McGowan SJ, Twigg SRF, Mathijssen IMJ, Nellaker C, Brunner HG, Wilkie AOM (2018) De novo and inherited loss-of-function variants in TLK2: clinical and genotype–phenotype evaluation of a distinct neurodevelopmental disorder. Am J Hum Genet 102(6):1195–1203. https://doi.org/10.1016/j.ajhg.2018.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Takata A, Miyake N, Tsurusaki Y, Fukai R, Miyatake S, Koshimizu E, Kushima I, Okada T, Morikawa M, Uno Y, Ishizuka K, Nakamura K, Tsujii M, Yoshikawa T, Toyota T, Okamoto N, Hiraki Y, Hashimoto R, Yasuda Y, Saitoh S, Ohashi K, Sakai Y, Ohga S, Hara T, Kato M, Nakamura K, Ito A, Seiwa C, Shirahata E, Osaka H, Matsumoto A, Takeshita S, Tohyama J, Saikusa T, Matsuishi T, Nakamura T, Tsuboi T, Kato T, Suzuki T, Saitsu H, Nakashima M, Mizuguchi T, Tanaka F, Mori N, Ozaki N, Matsumoto N (2018) Integrative analyses of de novo mutations provide deeper biological insights into autism spectrum disorder. Cell Rep 22(3):734–747. https://doi.org/10.1016/j.celrep.2017.12.074

    Article  CAS  PubMed  Google Scholar 

  91. Kelemen LE, Wang X, Fredericksen ZS, Pankratz VS, Pharoah PD, Ahmed S, Dunning AM, Easton DF, Vierkant RA, Cerhan JR, Goode EL, Olson JE, Couch FJ (2009) Genetic variation in the chromosome 17q23 amplicon and breast cancer risk. Cancer Epidemiol Biomark Prev 18(6):1864–1868. https://doi.org/10.1158/1055-9965.EPI-08-0486

    Article  CAS  Google Scholar 

  92. Stevens KN, Wang X, Fredericksen Z, Pankratz VS, Cerhan J, Vachon CM, Olson JE, Couch FJ (2011) Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. Breast Cancer Res Treat 129(2):617–622. https://doi.org/10.1007/s10549-011-1587-y

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kim JA, Tan Y, Wang X, Cao X, Veeraraghavan J, Liang Y, Edwards DP, Huang S, Pan X, Li K, Schiff R, Wang XS (2016) Comprehensive functional analysis of the tousled-like kinase 2 frequently amplified in aggressive luminal breast cancers. Nat Commun 7:12991. https://doi.org/10.1038/ncomms12991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, Wang X, Qiao JW, Cao S, Petralia F, Kawaler E, Mundt F, Krug K, Tu Z, Lei JT, Gatza ML, Wilkerson M, Perou CM, Yellapantula V, Huang KL, Lin C, McLellan MD, Yan P, Davies SR, Townsend RR, Skates SJ, Wang J, Zhang B, Kinsinger CR, Mesri M, Rodriguez H, Ding L, Paulovich AG, Fenyo D, Ellis MJ, Carr SA (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534(7605):55–62. https://doi.org/10.1038/nature18003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Singh V, Jaiswal PK, Ghosh I, Koul HK, Yu X, De Benedetti A (2019) The TLK1-Nek1 axis promotes prostate cancer progression. Cancer Lett 453:131–141. https://doi.org/10.1016/j.canlet.2019.03.041

    Article  CAS  PubMed  Google Scholar 

  96. Singh V, Jaiswal PK, Ghosh I, Koul HK, Yu X, De Benedetti A (2019) Targeting the TLK1/NEK1 DDR axis with thioridazine suppresses outgrowth of androgen independent prostate tumors. Int J Cancer. https://doi.org/10.1002/ijc.32200

    Article  PubMed  PubMed Central  Google Scholar 

  97. Takayama Y, Kokuryo T, Yokoyama Y, Ito S, Nagino M, Hamaguchi M, Senga T (2010) Silencing of Tousled-like kinase 1 sensitizes cholangiocarcinoma cells to cisplatin-induced apoptosis. Cancer Lett 296(1):27–34. https://doi.org/10.1016/j.canlet.2010.03.011

    Article  CAS  PubMed  Google Scholar 

  98. Hu S, Wang H, Yan D, Lu W, Gao P, Lou W, Kong X (2018) Loss of miR-16 contributes to tumor progression by activation of tousled-like kinase 1 in oral squamous cell carcinoma. Cell Cycle 17(18):2284–2295. https://doi.org/10.1080/15384101.2018.1526601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ronald S, Awate S, Rath A, Carroll J, Galiano F, Dwyer D, Kleiner-Hancock H, Mathis JM, Vigod S, De Benedetti A (2013) Phenothiazine inhibitors of TLKs affect double-strand break repair and DNA damage response recovery and potentiate tumor killing with radiomimetic therapy. Genes Cancer 4(1–2):39–53. https://doi.org/10.1177/1947601913479020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43(6):585–589. https://doi.org/10.1038/ng.835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H, Consortium on the Genetics of S, Group PS, Nimgaonkar VL, Go RC, Savage RM, Swerdlow NR, Gur RE, Braff DL, King MC, McClellan JM (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154(3):518–529. https://doi.org/10.1016/j.cell.2013.06.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, Georgieva L, Rees E, Palta P, Ruderfer DM, Carrera N, Humphreys I, Johnson JS, Roussos P, Barker DD, Banks E, Milanova V, Grant SG, Hannon E, Rose SA, Chambert K, Mahajan M, Scolnick EM, Moran JL, Kirov G, Palotie A, McCarroll SA, Holmans P, Sklar P, Owen MJ, Purcell SM, O’Donovan MC (2014) De novo mutations in schizophrenia implicate synaptic networks. Nature 506(7487):179–184. https://doi.org/10.1038/nature12929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimaki T, Lin CF, Ma’ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnstrom K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Ruther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Homozygosity Mapping Collaborative for A, Consortium UK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526):209–215. https://doi.org/10.1038/nature13772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA Jr, Kim R, Bilguvar K, Lopez-Giraldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WK (2015) De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350(6265):1262–1266. https://doi.org/10.1126/science.aac9396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. McKinnon PJ (2017) Genome integrity and disease prevention in the nervous system. Genes Dev 31(12):1180–1194. https://doi.org/10.1101/gad.301325.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Murga M, Bunting S, Montana MF, Soria R, Mulero F, Canamero M, Lee Y, McKinnon PJ, Nussenzweig A, Fernandez-Capetillo O (2009) A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat Genet 41(8):891–898. https://doi.org/10.1038/ng.420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. McNairn AJ, Chuang CH, Bloom JC, Wallace MD, Schimenti JC (2019) Female-biased embryonic death from inflammation induced by genomic instability. Nature 567(7746):105–108. https://doi.org/10.1038/s41586-019-0936-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lee J, Kim MS, Park SH, Jang YK (2018) Tousled-like kinase 1 is a negative regulator of core transcription factors in murine embryonic stem cells. Sci Rep 8(1):334. https://doi.org/10.1038/s41598-017-18628-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sadic D, Schmidt K, Groh S, Kondofersky I, Ellwart J, Fuchs C, Theis FJ, Schotta G (2015) Atrx promotes heterochromatin formation at retrotransposons. EMBO Rep 16(7):836–850. https://doi.org/10.15252/embr.201439937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Abrahams BS, Arking DE, Campbell DB, Mefford HC, Morrow EM, Weiss LA, Menashe I, Wadkins T, Banerjee-Basu S, Packer A (2013) SFARI gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol Autism 4(1):36. https://doi.org/10.1186/2040-2392-4-36

    Article  PubMed  PubMed Central  Google Scholar 

  111. Cipriani C, Ricceri L, Matteucci C, De Felice A, Tartaglione AM, Argaw-Denboba A, Pica F, Grelli S, Calamandrei G, Sinibaldi Vallebona P, Balestrieri E (2018) High expression of endogenous retroviruses from intrauterine life to adulthood in two mouse models of autism spectrum disorders. Sci Rep 8(1):629. https://doi.org/10.1038/s41598-017-19035-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M (2013) Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309(16):1696–1703. https://doi.org/10.1001/jama.2013.2270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T, Babor M, Quesnel-Vallieres M, Tapial J, Raj B, O’Hanlon D, Barrios-Rodiles M, Sternberg MJ, Cordes SP, Roth FP, Wrana JL, Geschwind DH, Blencowe BJ (2014) A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159(7):1511–1523. https://doi.org/10.1016/j.cell.2014.11.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Quesnel-Vallieres M, Dargaei Z, Irimia M, Gonatopoulos-Pournatzis T, Ip JY, Wu M, Sterne-Weiler T, Nakagawa S, Woodin MA, Blencowe BJ, Cordes SP (2016) Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mol Cell 64(6):1023–1034. https://doi.org/10.1016/j.molcel.2016.11.033

    Article  CAS  PubMed  Google Scholar 

  115. Gonatopoulos-Pournatzis T, Wu M, Braunschweig U, Roth J, Han H, Best AJ, Raj B, Aregger M, O’Hanlon D, Ellis JD, Calarco JA, Moffat J, Gingras AC, Blencowe BJ (2018) Genome-wide CRISPR-Cas9 interrogation of splicing networks reveals a mechanism for recognition of autism-misregulated neuronal microexons. Mol Cell 72(3):510–524. https://doi.org/10.1016/j.molcel.2018.10.008

    Article  CAS  PubMed  Google Scholar 

  116. Guo R, Zheng L, Park JW, Lv R, Chen H, Jiao F, Xu W, Mu S, Wen H, Qiu J, Wang Z, Yang P, Wu F, Hui J, Fu X, Shi X, Shi YG, Xing Y, Lan F, Shi Y (2014) BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol Cell 56(2):298–310. https://doi.org/10.1016/j.molcel.2014.08.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jimeno-Gonzalez S, Payan-Bravo L, Munoz-Cabello AM, Guijo M, Gutierrez G, Prado F, Reyes JC (2015) Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing. Proc Natl Acad Sci USA 112(48):14840–14845. https://doi.org/10.1073/pnas.1506760112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Xie J, Huang L, Li X, Li H, Zhou Y, Zhu H, Pan T, Kendrick KM, Xu W (2017) Immunological cytokine profiling identifies TNF-alpha as a key molecule dysregulated in autistic children. Oncotarget 8(47):82390–82398. https://doi.org/10.18632/oncotarget.19326

    Article  PubMed  PubMed Central  Google Scholar 

  119. Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, Hoeffer CA, Littman DR, Huh JR (2016) The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351(6276):933–939. https://doi.org/10.1126/science.aad0314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, Longman RS, Honda K, Littman DR, Choi GB, Huh JR (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549(7673):528–532. https://doi.org/10.1038/nature23910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana MF, D’Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O (2011) Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18(12):1331–1335. https://doi.org/10.1038/nsmb.2189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Carpentier PA, Dingman AL, Palmer TD (2011) Placental TNF-alpha signaling in illness-induced complications of pregnancy. Am J Pathol 178(6):2802–2810. https://doi.org/10.1016/j.ajpath.2011.02.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to members of the Stracker lab and A. Groth for discussions of unpublished data and suggestions. We apologize to those colleagues whose relevant work could not be specifically mentioned due to space constraints.

Funding

THS was funded by the Spanish Ministry of Science, Innovation and Universities (BFU2015-68354/GENPATH, PGC2018-095616-B-100/GINDATA and FEDER, the Centres of Excellence Severo Ochoa award and the CERCA Programme. SSB was funded by a PhD fellowship and the project LCF/PR/GN14/10270002 from the “la Caixa” Foundation.

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    Present address: The Francis Crick Institute, London, UK

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  1. Department of Oncology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, C/Baldiri Reixac 10, 08028, Barcelona, Spain

    Sandra Segura-Bayona & Travis H. Stracker

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Segura-Bayona, S., Stracker, T.H. The Tousled-like kinases regulate genome and epigenome stability: implications in development and disease. Cell. Mol. Life Sci. 76, 3827–3841 (2019). https://doi.org/10.1007/s00018-019-03208-z

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