Skip to main content
SpringerLink
Log in

Rif1, a Conserved Chromatin Factor Regulating DNA Replication, DNA Repair, and Transcription

  • Chapter
  • First Online:
The Initiation of DNA Replication in Eukaryotes

Abstract

Rif1, originally discovered as a telomere binding factor in yeast, is evolutionally conserved and regulates various aspects of chromosome reactions including repair, DNA replication, and transcription in addition to telomere regulation. In mammals, Rif1 suppresses homologous recombination-dependent repair and stimulates non-homologous end-joining repair of double-stranded DNA breaks. Rif1 plays a crucial role in regulating timing of genome replication during S phase. It also affects the transcription profiles. Rif1, composed of the N-terminal HEAT repeat domain and the C-terminal DNA binding/oligomerization domain, tightly binds to chromatin and may facilitate the formation of chromatin domains that may be repressive for initiation of replication as well as for transcription. Rif1 also binds to many factors including protein phosphatase 1, which plays a role in suppression of origin firing. Rif1 is expressed at a high level in mouse embryonic stem (ES) cells and is involved in regulation of differentiation processes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Masai H, Matsumoto S, You Z, Yoshizawa-Sugata N, Oda M. Eukaryotic chromosome DNA replication: where, when, and how? Annu Rev Biochem. 2010;79:89–130.

    Article  CAS  PubMed  Google Scholar 

  2. Yamazaki S, Hayano M, Masai H. Replication timing regulation of eukaryotic replicons: Rif1 as a global regulator of replication timing. Trends Genet. 2013;29(8):449–60.

    Article  CAS  PubMed  Google Scholar 

  3. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem. 2004;73:177–208.

    Article  CAS  PubMed  Google Scholar 

  4. Hardy CF, Balderes D, Shore D. Dissection of a carboxy-terminal region of the yeast regulatory protein RAP1 with effects on both transcriptional activation and silencing. Mol Cell Biol. 1992;12(3):1209–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Wotton D, Shore D. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev. 1997;11(6):748–60.

    Article  CAS  PubMed  Google Scholar 

  6. Levy DL, Blackburn EH. Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length. Mol Cell Biol. 2004;24(24):10857–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Lydall D, Weinert T. Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science. 1995;270(5241):1488–91.

    Article  CAS  PubMed  Google Scholar 

  8. Garvik B, Carson M, Hartwell L. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol Cell Biol. 1995;15(11):6128–38.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Xue Y, Rushton MD, Maringele L. A novel checkpoint and RPA inhibitory pathway regulated by Rif1. PLoS Genet. 2011;7(12):e1002417.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Anbalagan S, Bonetti D, Lucchini G, Longhese MP. Rif1 supports the function of the CST complex in yeast telomere capping. PLoS Genet. 2011;7(3):e1002024.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Iglesias N, Redon S, Pfeiffer V, Dees M, Lingner J, Luke B. Subtelomeric repetitive elements determine TERRA regulation by Rap1/Rif and Rap1/Sir complexes in yeast. EMBO Rep. 2011;12(6):587–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Kanoh J, Ishikawa F. spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast. Curr Biol. 2001;11(20):1624–30.

    Article  CAS  PubMed  Google Scholar 

  13. Miyoshi T, Kanoh J, Saito M, Ishikawa F. Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science. 2008;320(5881):1341–4.

    Article  CAS  PubMed  Google Scholar 

  14. Hayano M, Kanoh Y, Matsumoto S, Renard-Guillet C, Shirahige K, Masai H. Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes Dev. 2012;26(2):137–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Silverman J, Takai H, Buonomo SB, Eisenhaber F, de Lange T. Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev. 2004;18(17):2108–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Xu L, Blackburn EH. Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules. J Cell Biol. 2004;167(5):819–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Dan J, Liu Y, Liu N, Chiourea M, Okuka M, Wu T, et al. Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing. Dev Cell. 2014;29(1):7–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Buonomo SB, Wu Y, Ferguson D, de Lange T. Mammalian Rif1 contributes to replication stress survival and homology-directed repair. J Cell Biol. 2009;187(3):385–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, et al. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature. 2010;464(7290):858–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Sreesankar E, Senthilkumar R, Bharathi V, Mishra RK, Mishra K. Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes. BMC Genomics. 2012;13:255.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Peace JM, Ter-Zakarian A, Aparicio OM. Rif1 regulates initiation timing of late replication origins throughout the S. cerevisiae genome. PLoS One. 2014;9(5):e98501.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Davé A, Cooley C, Garg M, Bianchi A. Protein phosphatase 1 recruitment by Rif1 regulates DNA replication origin firing by counteracting DDK activity. Cell Rep. 2014;7(1):53–61.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Hiraga S, Alvino GM, Chang F, Lian HY, Sridhar A, Kubota T, et al. Rif1 controls DNA replication by directing protein phosphatase 1 to reverse Cdc7-mediated phosphorylation of the MCM complex. Genes Dev. 2014;28(4):372–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Mattarocci S, Shyian M, Lemmens L, Damay P, Altintas DM, Shi T, et al. Rif1 controls DNA replication timing in yeast through the PP1 phosphatase Glc7. Cell Rep. 2014;7(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  25. Tazumi A, Fukuura M, Nakato R, Kishimoto A, Takenaka T, Ogawa S, et al. Telomere-binding protein Taz1 controls global replication timing through its localization near late replication origins in fission yeast. Genes Dev. 2012;26(18):2050–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Park S, Patterson EE, Cobb J, Audhya A, Gartenberg MR, Fox CA. Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1. Proc Natl Acad Sci U S A. 2011;108(35):14572–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ebrahimi H, Robertson ED, Taddei A, Gasser SM, Donaldson AD, Hiraga S. Early initiation of a replication origin tethered at the nuclear periphery. J Cell Sci. 2010;123(Pt 7):1015–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Cornacchia D, Dileep V, Quivy JP, Foti R, Tili F, Santarella-Mellwig R, et al. Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J. 2012;31(18):3678–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Yamazaki S, Ishii A, Kanoh Y, Oda M, Nishito Y, Masai H. Rif1 regulates the replication timing domains on the human genome. EMBO J. 2012;31(18):3667–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Gilbert DM. Cell fate transitions and the replication timing decision point. J Cell Biol. 2010;191(5):899–903.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol Cell. 2013;49(5):858–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M, Gitlin AD, et al. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science. 2013;339(6120):711–5.

    Article  PubMed  Google Scholar 

  33. Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT, Tkac J, et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell. 2013;49(5):872–83.

    Article  CAS  PubMed  Google Scholar 

  34. Feng L, Fong KW, Wang J, Wang W, Chen J. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J Biol Chem. 2013;288(16):11135–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science. 2013;339(6120):700–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Martina M, Bonetti D, Villa M, Lucchini G, Longhese MP. Saccharomyces cerevisiae Rif1 cooperates with MRX-Sae2 in promoting DNA-end resection. EMBO Rep. 2014;15(6):695–704. PMCID: PMC4197880. eng.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Xu D, Muniandy P, Leo E, Yin J, Thangavel S, Shen X, et al. Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. EMBO J. 2010;29(18):3140–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Grabarz A, Guirouilh-Barbat J, Barascu A, Pennarun G, Genet D, Rass E, et al. A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining. Cell Rep. 2013;5(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  39. Wu W, Nishikawa H, Fukuda T, Vittal V, Asano M, Miyoshi Y, et al. Interaction of BARD1 and HP1 is required for BRCA1 retention at sites of DNA damage. Cancer Res. 2015;75(7):1311–21.

    Article  CAS  PubMed  Google Scholar 

  40. Difilippantonio S, Gapud E, Wong N, Huang CY, Mahowald G, Chen HT, et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature. 2008;456(7221):529–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Adams IR, McLaren A. Identification and characterisation of mRif1: a mouse telomere-associated protein highly expressed in germ cells and embryo-derived pluripotent stem cells. Dev Dyn. 2004;229(4):733–44.

    Article  CAS  PubMed  Google Scholar 

  42. Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 2006;38(4):431–40.

    Article  CAS  PubMed  Google Scholar 

  43. Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006;444(7117):364–8.

    Article  CAS  PubMed  Google Scholar 

  44. Daxinger L, Harten SK, Oey H, Epp T, Isbel L, Huang E, et al. An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse. Genome Biol. 2013;14(9):R96.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Kim J, Chu J, Shen X, Wang J, Orkin SH. An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 2008;132(6):1049–61.

    Article  CAS  PubMed  Google Scholar 

  46. Fazzio TG, Huff JT, Panning B. An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity. Cell. 2008;134(1):162–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Li P, Ma X, Adams IR, Yuan P. A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability. Cell Death Dis. 2015;6:e1588.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9. PMCID: PMC3760771. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Simon JA, Kingston RE. Occupying chromatin: polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell. 2013;49(5):808–24. PMCID: PMC3628831. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Macfarlan TS, Gifford WD, Agarwal S, Driscoll S, Lettieri K, Wang J, et al. Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes Dev. 2011;25(6):594–607.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Sukackaite R, Jensen MR, Mas PJ, Blackledge M, Buonomo SB, Hart DJ. Structural and biophysical characterization of murine rif1 C terminus reveals high specificity for DNA cruciform structures. J Biol Chem. 2014;289(20):13903–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Shi T, Bunker RD, Mattarocci S, Ribeyre C, Faty M, Gut H, et al. Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. Cell. 2013;153(6):1340–53.

    Article  CAS  PubMed  Google Scholar 

  53. Moorhead GB, Trinkle-Mulcahy L, Nimick M, De Wever V, Campbell DG, Gourlay R, et al. Displacement affinity chromatography of protein phosphatase one (PP1) complexes. BMC Biochem. 2008;9:28.

    Article  PubMed Central  PubMed  Google Scholar 

  54. McEachern MJ, Blackburn EH. A conserved sequence motif within the exceptionally diverse telomeric sequences of budding yeasts. Proc Natl Acad Sci U S A. 1994;91(8):3453–7. PMCID: PMC43595. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Sugawara N. DNA sequences at the telomeres of fission yeast S. pombe [PhD thesis]. Harvard University; 1989.

    Google Scholar 

  56. Joseph I, Lustig AJ. Telomeres in meiotic recombination: the yeast side story. Cell Mol Life Sci. 2007;64(2):125–30.

    Article  CAS  PubMed  Google Scholar 

  57. Meyne J, Ratliff RL, Moyzis RK. Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc Natl Acad Sci U S A. 1989;86(18):7049–53. PMCID: PMC297991. eng.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Dewar JM, Lydall D. Similarities and differences between “uncapped” telomeres and DNA double-strand breaks. Chromosoma. 2012;121(2):117–30.

    Article  CAS  PubMed  Google Scholar 

  59. Kanoh Y, Matsumoto S, Fukatsu R, Kakusho N, Kono N, Renard-Guillet C et al. Rif1 binds to G quadruplexes and suppresses replication over long distances. Nat Struct Mol Biol. in press.

    Google Scholar 

Download references

Acknowledgements

We would like to thank members of our laboratory for collaboration and useful discussion.

Author information

Authors and Affiliations

  1. Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Naoko Yoshizawa-Sugata, Satoshi Yamazaki & Hisao Masai

Authors
  1. Naoko Yoshizawa-Sugata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoshi Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisao Masai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hisao Masai .

Editor information

Editors and Affiliations

  1. Florida State Univ. College of Medi, TALLAHASSEE, Florida, USA

    Daniel L. Kaplan

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Yoshizawa-Sugata, N., Yamazaki, S., Masai, H. (2016). Rif1, a Conserved Chromatin Factor Regulating DNA Replication, DNA Repair, and Transcription. In: Kaplan, D. (eds) The Initiation of DNA Replication in Eukaryotes. Springer, Cham. https://doi.org/10.1007/978-3-319-24696-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation