Skip to main content
SpringerLink
Log in

Kinase Cascade of DNA Damage Checkpoint

  • Chapter
  • First Online:
Genetics, Evolution and Radiation

  • 867 Accesses

Abstract

Molecular mechanisms of activation of DNA repair and checkpoint by double-strand breaks are considered. They include phosphorylation by protein kinases of repair and checkpoint proteins resulting in their activation, alteration of affinity to other proteins, and changes of their localization.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
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

  • Ahnesorg P, Jackson SP (2007) The non-homologous end-joining protein Nej1p is a target of the DNA damage checkpoint. DNA Repair 6:190–201 (Amst)

    Article  CAS  PubMed  Google Scholar 

  • Alcasabas AA, Osborn AJ, Bachant J et al (2001) Mrc1 transduces signals of DNA replication stress to activate Rad53. Nat Cell Biol 3:958–965

    Article  CAS  PubMed  Google Scholar 

  • Aylon Y, Kupiec M (2005) Cell cycle-dependent regulation of double-strand break repair: a role for the CDK. Cell Cycle 4:E61–E63

    Article  Google Scholar 

  • Bartova I, Otyepka M, Kriz Z, Koca J (2004) Activation and inhibition of cyclin-dependent kinase-2 by phosphorylation: a molecular dynamics study reveals the functional importance of the glycine-rich loop. Protein Sci 13:1449–1457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartrand AJ, Iyasu D, Brush GS (2004) DNA stimulates Mec1-mediated phosphorylation of replication protein A. J Biol Chem 279:2762–26767

    Article  Google Scholar 

  • Bashkirov VI, King JS, Bashkirova EV et al (2000) DNA repair protein Rad55 Is a terminal substrate of the DNA damage checkpoints. Mol Cell Biol 20:4393–4404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bashkirov VI, Bashkirova EV, Haghnazari E, Heyer WD (2003) Direct kinase-to-kinase signaling mediated by the FHA phosphoprotein recognition domain of the Dun1 DNA damage checkpoint kinase. Mol Cell Biol 23:1441–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blankley RT, Lydall D (2004) A Domain of Rad9 specifically required for activation of Chk1 in budding yeast. J Cell Sci 117:601–608

    Article  CAS  PubMed  Google Scholar 

  • Bosch M, Lowndes NF (2004) Remodelling the Rad9 checkpoint complex: preparing Rad53 for Action. Cell Cycle 3:119–122

    Article  PubMed  Google Scholar 

  • Brush GS, Kelly TJ (2000) Phosphorylation of the replication protein a large subunit in the saccharomyces cerevisiae checkpoint response. Nucleic Acids Res 28:3725–3732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brush GS, Morrow DM, Hieter P, Kelly TJ (1996) The ATM homologue MEC1 is required for phosphorylation of replication protein A in yeast. Proc Natl Acad Sci USA 93:15075–15080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brusky J, Zhu Y, Xiao W (2000) UBC13, a DNA-damage-inducible gene, is a member of the error-free postreplication repair pathway in saccharomyces cerevisiae. Curr Genet 37:168–174

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Sanchez Y (2004) Chk1 in the DNA damage response: conserved roles from yeasts to mammals. DNA Repair 3:1025–1032 (Amst)

    Article  CAS  PubMed  Google Scholar 

  • Chen SH, Smolka MB, Zhou H (2007) Mechanism of Dun1 activation by Rad53 phosphorylation in saccharomyces cerevisiae. J Biol Chem 282:986–995

    Article  CAS  PubMed  Google Scholar 

  • Chiolo I, Carotenuto W, Maffioletti G et al (2005) Srs2 and Sgs1 DNA helicases associate with Mre11 in different subcomplexes following checkpoint activation and CDK1-mediated Srs2 phosphorylation. Mol Cell Biol 25:5738–5751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deide SJ, Gottschling DE (2001) Exonuclease activity is required for sequence addition and Cdc13p loading at a de novo telomere. Curr Biol 11:1336–1340

    Article  Google Scholar 

  • Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4:387–394

    Article  CAS  PubMed  Google Scholar 

  • Elledge SJ (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274:1664–1672

    Article  CAS  PubMed  Google Scholar 

  • Ellison V, Stillman B (2003) Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5’ recessed DNA. PLoS Biol 1:E33

    Article  PubMed  PubMed Central  Google Scholar 

  • Emili A (1998) MEC1-dependent phosphorylation of Rad9p in response to DNA damage. Mol Cell 2:183–189

    Article  CAS  PubMed  Google Scholar 

  • Fay DS, Sun Z, Stern DF (1997) Mutations in SPK1/RAD53 that specifically abolish checkpoint but not growth-related functions. Curr Genet 31:97–105

    Article  CAS  PubMed  Google Scholar 

  • Gardner R, Putnam CW, Weinert T (1999) RAD53, DUN1 and PDS1 define two parallel G2/M checkpoint pathways in budding yeast. EMBO J 18:3173–3185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garvik B, Carson M, Hartwell L (1995) Single-stranded dna arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol Cell Biol 15:6128–6138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gavin AC, Aloy P, Grandi P et al (2006) Proteome survey reveals modularity of the yeast cell machinery. Nature 440:631–636

    Article  CAS  PubMed  Google Scholar 

  • Gaziev AI (1999) DNA damage in cells exposed to ionizing radiation. Radiats Biol Radioekol 39:630–638

    CAS  Google Scholar 

  • Gilbert CS, Green CM, Lowndes NF (2001) Budding yeast Rad9 is an ATP-dependent Rad53 activating machine. Mol Cell 8:129–136

    Article  CAS  PubMed  Google Scholar 

  • Glazer VM, Glazunov AV (1999) Molecular genetic analysis of DNA double-strand break repair in yeast saccharomycetes. Russ J Genet 35:1449–1469

    CAS  Google Scholar 

  • Grandin N, Charbonneau M (2003) Mitotic cyclins regulate telomeric recombination in telomerase-deficient yeast cells. Mol Cell Biol 23:9162–9177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green CM, Erdjument-Bromage H, Tempst P, Lowndes NF (2000) A novel Rad24 checkpoint protein complex closely related to replication factor C. Curr Biol 10:39–42

    Article  CAS  PubMed  Google Scholar 

  • Gusev NB (2000) Proteinkinases: structure, classification, properties and biological role. Soros Obraz Zh 6:4–12

    Google Scholar 

  • Hammet A, Pike BL, Heierhorst J (2002) Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2–Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. J Biol Chem 277:22469–22474

    Article  CAS  PubMed  Google Scholar 

  • Herzberg K, Bashkirov VI, Rolfsmeier M et al (2006) Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks. Mol Cell Biol 26:8396–8409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeksta MF, Demaggio AJ, Dhillon N (1991a) Genetically identified protein kinases in yeast: I. Transcription, translation, transport and mating. Trends Genet 7:256–261

    Google Scholar 

  • Hoeksta MF, Demaggio AJ, Dhillon N (1991b) Genetically identified protein kinases in yeast: II. DNA metabolism and meiosis. Trends Genet 7:293–297

    Google Scholar 

  • Huang M, Zhou Z, Elledge SJ (1998) The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor. Cell 94:595–605

    Article  CAS  PubMed  Google Scholar 

  • Ira G, Pellicioli A, Balijja A et al (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431:1011–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur R, Kostrub CF, Enoch T (2001) Structure–function analysis of fission yeast Hus1-Rad1-Rad9 checkpoint complex. Mol Biol Cell 12:3744–3758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kholmurodov KhT, Kretov DA, Gerasimova AS, Koltovaya NA (2006) Molecular dynamics simulation of replacing of conserved glycine by serine in the G-loop in the cdc28-srm yeast mutant using the crystal lattice of human CDK2 kinase. Biofizika 51:679–691

    CAS  PubMed  Google Scholar 

  • Kim S, Weinert TA (1997) Characterization of the checkpoint gene RAD53/MEC2 in Saccharomyces cerevisiae. Yeast 13:735–745

    Article  CAS  PubMed  Google Scholar 

  • Kim HS, Brill SJ (2003) MEC1-dependent phosphorylation of yeast RPA1 in vitro. DNA Repair 2:1321–1335 (Amst)

    Article  CAS  PubMed  Google Scholar 

  • Kim ST, Lim DS, Canman CE, Kastan MB (1999) Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem 274:3738–3743

    Google Scholar 

  • Kleiman FE, Manley JL (2001) The BARD1-CstF-50 interaction links mRNA 3’ end formation to DNA damage and tumor suppression. Cell 104:743–753

    Article  CAS  PubMed  Google Scholar 

  • Korolev VG (2007) Molecular mechanisms of DNA double-strand break repair in eukaryotes. Radiats Biol Radioekol 47:389–401

    CAS  Google Scholar 

  • Lee SE, Moore JK, Holmes A et al (1998) Ku70, Mre11/Rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94:399–409

    Article  CAS  PubMed  Google Scholar 

  • Lee SE, Paques F, Sylvan J, Haber JE (1999) Role of yeast SIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths. Curr Biol 9:767–770

    Article  CAS  PubMed  Google Scholar 

  • Leroy C, Lee SE, Vaze MB et al (2003) PP2C phosphatases Ptc2 and Ptc3 are required for DNA checkpoint inactivation after a double-strand break. Mol Cell 11:827–835

    Article  CAS  PubMed  Google Scholar 

  • Liao H, Byeon IJ, Tsai MD (1999) Structure and Function of a New Phosphopeptide-Binding Domain Containing the FHA2 of Rad53. J Mol Biol 294:1041–1049

    Article  CAS  PubMed  Google Scholar 

  • Liberi G, Chiolo I, Pellicioli A et al (2000) Srs2 DNA helicase is involved in checkpoint response and its regulation requires a functional Mec1-dependent pathway and Cdk1 activity. EMBO J 19:5027–5038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A (2001) Purification and characterization of human DNA damage checkpoint Rad complexes. Proc Natl Acad Sci USA 98:11236–11241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longhese MP, Fraschini R, Plevani P, Lucchini G (1996) Yeast pip3/mec3 mutants fail to delay entry into S phase and to slow DNA replication in response to DNA damage, and they define a functional link between Mec3 and DNA primase. Mol Cell Biol 16:3235–3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Longhese MP, Foiani M, Muzi-Falconi M et al (1998) DNA damage checkpoint in budding yeast. EMBO J 17:5525–5528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma JL, Lee SJ, Duong JK, Stern DF (2006) Activation of the checkpoint kinase Rad53 by the phosphatidyl inositol kinase-like kinase Mec1. J Biol Chem 281:3954–3963

    Article  CAS  PubMed  Google Scholar 

  • Majka J, Burgers PM (2003) Yeast Rad17/Mec3/Ddc1: a sliding clamp for the DNA damage checkpoint. Proc Natl Acad Sci USA 100:2249–2254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15:2809–2821

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mendenhall MD, Hodge AE (1998) Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast. Micriobiol Mol Biol Rev 62:1191–1243

    CAS  Google Scholar 

  • Morrow DM, Tagle DA, Shiloh Y et al (1995) TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82:831–840

    Article  CAS  PubMed  Google Scholar 

  • Naiki T, Wakayama T, Nakada D et al (2004) Association of Rad9 with double-strand breaks through a Mec1-dependent mechanism. Mol Cell Biol 24:3277–3285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakada D, Shimomura T, Matsumoto K, Sugimoto K (2003) The ATM-related Tel1 protein of Saccharomyces cerevisiae controls a checkpoint response following phleomycin treatment. Nucleic Acids Res 31:1715–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakada D, Hirano Y, Tanaka Y, Sugimoto K (2005) Role of the C-terminus of Mec1 checkpoint kinase in its localization to sites of DNA damage. Mol Biol Cell 16:5227–5235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osborn AJ, Elledge SJ (2003) Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Genes Dev 17:1755–1767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pati D, Keller C, Groundine M, Plon SE (1997) Reconstitution of a MEC1-independent checkpoint in yeast by expression of a novel human fork head cDNA. Mol Cell Biol 17:3037–3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raymond WE, Kleckner N (1993) RAD50 Protein of S. cerevisiae exhibits ATP-dependent DNA binding. Mol Gen Genet 238:390–400

    Article  CAS  PubMed  Google Scholar 

  • Robison JG, Elliott J, Dixon K, Oakley GG (2004) Replication protein A and the Mre11-Rad50-Nbs1 complex co-localize and interact at sites of stalled replication forks. J Biol Chem 279:34802–34810

    Article  CAS  PubMed  Google Scholar 

  • Rouse J, Jackson SP (2002) Interfaces between the detection, signaling, and repair of DNA damage. Science 297:547–551

    Article  CAS  PubMed  Google Scholar 

  • Sanchez Y, Desany BA, Jones WJ et al (1996) Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271:357–360

    Article  CAS  PubMed  Google Scholar 

  • Sanchez Y, Bachant J, Wang H et al (1999) Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science 286:1166–1171

    Article  CAS  PubMed  Google Scholar 

  • Schollaert K, Poisson J, Searle JJ et al (2004) A role for Saccharomyces cerevisiae Chk1p in the response to replication blocks. Mol Biol Cell 15:4051–4063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwartz MF, Duong JF, Sun Z et al (2002) Rad9 phosphorylation sites couple Rad53 to the Saccharomyces cerevisiae DNA damage checkpoint. Mol Cell 9:1055–1065

    Article  CAS  PubMed  Google Scholar 

  • Sidorova JM, Breeden LL (1997) Rad53-dependent phosphorylation of Swi6 and down-regulation of CLN1 and CLN2 transcription occur in response to DNA damage in Saccharomyces cerevisiae. Genes Dev 11:3032–3045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soulier J, Lowndes NF (1999) The BRCT domain of the S. cerevisiae checkpoint protein Rad9 mediates a Rad9–Rad9 interaction after DNA damage. Curr Biol 9:551–554

    Article  CAS  PubMed  Google Scholar 

  • Sun Z, Hsiao J, Fay DS, Stern DF (1998) Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. Science 281:272–274

    Article  CAS  PubMed  Google Scholar 

  • Sweeney FD, Yang F, Chi A et al (2005) Saccharomyces cerevisiae Rad9 acts as a Mec1 adaptor to allow Rad53 activation. Curr Biol 15:1364–1375

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Russell P (2001) Mrc1 channels the DNA replication arrest Signal to checkpoint kinase Cds1. Nat Cell Biol 3:966–972

    Article  CAS  PubMed  Google Scholar 

  • Tsukamoto Y, Mitsuoka C, Terasawa M et al (2005) Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination. Mol Biol Cell 16:597–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ubersax JA, Woodbury EL, Quang PN et al (2003) Targets of the cyclin-dependent kinase Cdk1. Nature 425:859–864

    Article  CAS  PubMed  Google Scholar 

  • Ulrich HD, Jentsch S (2000) Two RING finger proteins mediate cooperation between ubiquitin-conjugating enzymes in DNA repair. EMBO J 19:3388–3397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vialard JE, Gilbert CS, Green CM, Lowndes NF (1998) The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage. EMBO J 17:5679–5688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinert T (1998) DNA damage checkpoints update: getting molecular. Curr Opin Genet Dev 8:185–193

    Article  CAS  PubMed  Google Scholar 

  • Xiao W, Chow B, Broomfield S, Hanna M (2000) The Saccharomyces cerevisiae RAD6 group is composed of an error-prone and two error-free postreplication repair pathways. Genetics 155:1633–1641

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao X, Rothstein R (2002) The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Proc Natl Acad Sci USA 99:3746–3751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Z, Elledge SJ (1993) DUN1 encodes a protein kinase that controls the DNA damage response in yeast. Cell 75:1119–1127

    Article  CAS  PubMed  Google Scholar 

  • Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    Article  CAS  PubMed  Google Scholar 

  • Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA–ssDNA complexes. Science 300:1542–1548

    Article  CAS  PubMed  Google Scholar 

  • Zou L, Liu D, Elledge SJ (2003) Replication protein A—mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci USA 100:13827–13832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Joint Institute for Nuclear Research, Dubna, Russia

    Natalia Koltovaya

Authors
  1. Natalia Koltovaya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Natalia Koltovaya .

Editor information

Editors and Affiliations

  1. Joint Institute for Nuclear Research, Dubna, Moscow Region, Russia

    Victoria L. Korogodina

  2. Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada

    Carmel E Mothersill

  3. Genetics and Biotechnology, St. Petersburg State University, St. Petersburg, Russia

    Sergey G. Inge-Vechtomov

  4. Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario, Canada

    Colin B. Seymour

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing AG

About this chapter

Cite this chapter

Koltovaya, N. (2016). Kinase Cascade of DNA Damage Checkpoint. In: Korogodina, V., Mothersill, C., Inge-Vechtomov, S., Seymour, C. (eds) Genetics, Evolution and Radiation. Springer, Cham. https://doi.org/10.1007/978-3-319-48838-7_11

Download citation

Publish with us

Policies and ethics

Search

Navigation