Home LiteratureArticle Details
PMID: 15972456 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Brc1-mediated DNA repair and damage tolerance.

Genetics ·Vol. 171 ·No. 2 ·2005-10-00 ·Pages 457-68

Sheedy DM, Dimitrova D, Rankin JK, Bass KL, Lee KM, Tapia-Alveal C, Harvey SH, Murray JM, O'Connell MJ

Abstract

The structural maintenance of chromosome (SMC) proteins are key elements in controlling chromosome dynamics. In eukaryotic cells, three essential SMC complexes have been defined: cohesin, condensin, and the Smc5/6 complex. The latter is essential for DNA damage responses; in its absence both repair and checkpoint responses fail. In fission yeast, the UV-C and ionizing radiation (IR) sensitivity of a specific hypomorphic allele encoding the Smc6 subunit, rad18-74 (renamed smc6-74), is suppressed by mild overexpression of a six-BRCT-domain protein, Brc1. Deletion of brc1 does not result in a hypersensitivity to UV-C or IR, and thus the function of Brc1 relative to the Smc5/6 complex has remained unclear. Here we show that brc1Delta cells are hypersensitive to a range of radiomimetic drugs that share the feature of creating lesions that are an impediment to the completion of DNA replication. Through a genetic analysis of brc1Delta epistasis and by defining genes required for Brc1 to suppress smc6-74, we find that Brc1 functions to promote recombination through a novel postreplication repair pathway and the structure-specific nucleases Slx1 and Mus81. Activation of this pathway through overproduction of Brc1 bypasses a repair defect in smc6-74, reestablishing resolution of lesions by recombination.

MeSH Terms
Cell Cycle Proteins/genetics DNA Damage/genetics DNA Repair/genetics DNA-Binding Proteins/genetics,metabolism Endonucleases/genetics,metabolism Epistasis, Genetic Metronidazole/analogs & derivatives,toxicity Recombination, Genetic/genetics Schizosaccharomyces/drug effects,genetics,radiation effects Schizosaccharomyces pombe Proteins/genetics,metabolism Ultraviolet Rays
Chemicals
Brc1 protein, S pombe Cell Cycle Proteins DNA-Binding Proteins MUS81 protein, S pombe Schizosaccharomyces pombe Proteins smc6 protein, S pombe metronidazole monosuccinate Metronidazole Endonucleases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Sheedy Daniel M
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Dimitrova Dora
Rankin Jessica K
Bass Kirstin L
Lee Karen M
Tapia-Alveal Claudia
Harvey Susan H
Murray Johanne M
O'Connell Matthew J
References (63)
63 references, click to expand
  1. Chk1 is a wee1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation.
    EMBO J. 1997 Feb 3;16(3):545-54 PMID: 9034337
  2. A kinase from fission yeast responsible for blocking mitosis in S phase.
    Nature. 1995 Apr 27;374(6525):817-9 PMID: 7723827
  3. Role of Schizosaccharomyces pombe RecQ homolog, recombination, and checkpoint genes in UV damage tolerance.
    Mol Cell Biol. 1997 Dec;17(12):6868-75 PMID: 9372918
  4. Hus1p, a conserved fission yeast checkpoint protein, interacts with Rad1p and is phosphorylated in response to DNA damage.
    EMBO J. 1998 Apr 1;17(7):2055-66 PMID: 9524127
  5. Cut5 is a component of the UV-responsive DNA damage checkpoint in fission yeast.
    Mol Gen Genet. 1998 Dec;260(5):426-33 PMID: 9894912
  6. Rad18 is required for DNA repair and checkpoint responses in fission yeast.
    Mol Biol Cell. 1999 Sep;10(9):2905-18 PMID: 10473635
  7. Composition and architecture of the Schizosaccharomyces pombe Rad18 (Smc5-6) complex.
    Mol Cell Biol. 2005 Jan;25(1):172-84 PMID: 15601840
  8. Nse2, a component of the Smc5-6 complex, is a SUMO ligase required for the response to DNA damage.
    Mol Cell Biol. 2005 Jan;25(1):185-96 PMID: 15601841
  9. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain.
    Mol Cell. 2004 Dec 22;16(6):991-1002 PMID: 15610741
  10. Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair.
    Mol Cell. 2004 Dec 22;16(6):1003-15 PMID: 15610742
  11. Human PTIP facilitates ATM-mediated activation of p53 and promotes cellular resistance to ionizing radiation.
    J Biol Chem. 2004 Dec 31;279(53):55562-9 PMID: 15456759
  12. Characterization of Schizosaccharomyces pombe Hus1: a PCNA-related protein that associates with Rad1 and Rad9.
    Mol Cell Biol. 2000 Feb;20(4):1254-62 PMID: 10648611
  13. A recombination repair gene of Schizosaccharomyces pombe, rhp57, is a functional homolog of the Saccharomyces cerevisiae RAD57 gene and is phylogenetically related to the human XRCC3 gene.
    Genetics. 2000 Apr;154(4):1451-61 PMID: 10747044
  14. Fission yeast Eso1p is required for establishing sister chromatid cohesion during S phase.
    Mol Cell Biol. 2000 May;20(10):3459-69 PMID: 10779336
  15. The rad18 gene of Schizosaccharomyces pombe defines a new subgroup of the SMC superfamily involved in DNA repair.
    Mol Cell Biol. 1995 Dec;15(12):7067-80 PMID: 8524274
  16. Isolation of the Schizosaccharomyces pombe RAD54 homologue, rhp54+, a gene involved in the repair of radiation damage and replication fidelity.
    J Cell Sci. 1996 Jan;109 ( Pt 1):73-81 PMID: 8834792
  17. The Schizosaccharomyces pombe rad3 checkpoint gene.
    EMBO J. 1996 Dec 2;15(23):6641-51 PMID: 8978690
  18. The role of SMC proteins in the responses to DNA damage.
    DNA Repair (Amst). 2005 Mar 2;4(3):309-14 PMID: 15661654
  19. A SUMO ligase is part of a nuclear multiprotein complex that affects DNA repair and chromosomal organization.
    Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4777-82 PMID: 15738391
  20. SMC5 and SMC6 genes are required for the segregation of repetitive chromosome regions.
    Nat Cell Biol. 2005 Apr;7(4):412-9 PMID: 15793567
  21. Condensins: organizing and segregating the genome.
    Curr Biol. 2005 Apr 12;15(7):R265-75 PMID: 15823530
  22. Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function.
    Annu Rev Biochem. 2005;74:317-53 PMID: 15952890
  23. Review: SMCs in the world of chromosome biology- from prokaryotes to higher eukaryotes.
    J Struct Biol. 2000 Apr;129(2-3):123-43 PMID: 10806064
  24. Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1.
    Mol Cell Biol. 2000 Dec;20(23):8758-66 PMID: 11073977
  25. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae.
    Genetics. 2001 Jan;157(1):103-18 PMID: 11139495
  26. Involvement of Schizosaccharomyces pombe Srs2 in cellular responses to DNA damage.
    Nucleic Acids Res. 2001 Jul 15;29(14):2963-72 PMID: 11452021
  27. A homologue of the Rad18 postreplication repair gene is required for DNA damage responses throughout the fission yeast cell cycle.
    Mol Genet Genomics. 2001 Aug;265(6):993-1003 PMID: 11523791
  28. Functional overlap between Sgs1-Top3 and the Mms4-Mus81 endonuclease.
    Genes Dev. 2001 Oct 15;15(20):2730-40 PMID: 11641278
  29. The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair.
    Genes Dev. 2002 Feb 15;16(4):399-414 PMID: 11850403
  30. Structural maintenance of chromosomes (SMC) proteins, a family of conserved ATPases.
    Genome Biol. 2002;3(2):REVIEWS3003 PMID: 11864377
  31. The Schizosaccharomyces pombe rad60 gene is essential for repairing double-strand DNA breaks spontaneously occurring during replication and induced by DNA-damaging agents.
    Mol Cell Biol. 2002 May;22(10):3537-48 PMID: 11971984
  32. Cnd2 has dual roles in mitotic condensation and interphase.
    Nature. 2002 May 9;417(6885):197-202 PMID: 12000964
  33. Identification of a novel non-structural maintenance of chromosomes (SMC) component of the SMC5-SMC6 complex involved in DNA repair.
    J Biol Chem. 2002 Jun 14;277(24):21585-91 PMID: 11927594
  34. Mus81-Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks.
    J Biol Chem. 2002 Sep 6;277(36):32753-9 PMID: 12084712
  35. Checkpoint activation regulates mutagenic translesion synthesis.
    Genes Dev. 2003 Jan 1;17(1):64-76 PMID: 12514100
  36. Structural and functional conservation of error-free DNA postreplication repair in Schizosaccharomyces pombe.
    DNA Repair (Amst). 2002 Nov 3;1(11):869-80 PMID: 12531016
  37. BRCT domain-containing protein PTIP is essential for progression through mitosis.
    Mol Cell Biol. 2003 Mar;23(5):1666-73 PMID: 12588986
  38. High dosage Rhp51 suppression of the MMS sensitivity of DNA structure checkpoint mutants reveals a relationship between Crb2 and Rhp51.
    Genes Cells. 2003 Jul;8(7):573-86 PMID: 12839619
  39. Replication checkpoint kinase Cds1 regulates recombinational repair protein Rad60.
    Mol Cell Biol. 2003 Aug;23(16):5939-46 PMID: 12897162
  40. RecQ helicases: multiple roles in genome maintenance.
    Trends Cell Biol. 2003 Sep;13(9):493-501 PMID: 12946629
  41. The endogenous Mus81-Eme1 complex resolves Holliday junctions by a nick and counternick mechanism.
    Mol Cell. 2003 Sep;12(3):747-59 PMID: 14527419
  42. Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis.
    Mol Cell. 2003 Sep;12(3):761-74 PMID: 14527420
  43. BRCT repeats as phosphopeptide-binding modules involved in protein targeting.
    Science. 2003 Oct 24;302(5645):636-9 PMID: 14576432
  44. Novel essential DNA repair proteins Nse1 and Nse2 are subunits of the fission yeast Smc5-Smc6 complex.
    J Biol Chem. 2003 Nov 14;278(46):45460-7 PMID: 12966087
  45. Assigning function to yeast proteins by integration of technologies.
    Mol Cell. 2003 Dec;12(6):1353-65 PMID: 14690591
  46. Two different Swi5-containing protein complexes are involved in mating-type switching and recombination repair in fission yeast.
    Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15770-5 PMID: 14663140
  47. Slx1-Slx4 are subunits of a structure-specific endonuclease that maintains ribosomal DNA in fission yeast.
    Mol Biol Cell. 2004 Jan;15(1):71-80 PMID: 14528010
  48. Coordination of DNA damage responses via the Smc5/Smc6 complex.
    Mol Cell Biol. 2004 Jan;24(2):662-74 PMID: 14701739
  49. Recovery from DNA damage checkpoint arrest by PP1-mediated inhibition of Chk1.
    EMBO J. 2004 Feb 25;23(4):908-18 PMID: 14765108
  50. SMC6 is required for MMS-induced interchromosomal and sister chromatid recombinations in Saccharomyces cerevisiae.
    DNA Repair (Amst). 2004 Apr 1;3(4):429-39 PMID: 15010319
  51. Esc4p, a new target of Mec1p (ATR), promotes resumption of DNA synthesis after DNA damage.
    EMBO J. 2004 Mar 10;23(5):1188-97 PMID: 14988729
  52. Separase-mediated cleavage of cohesin at interphase is required for DNA repair.
    Nature. 2004 Aug 26;430(7003):1044-8 PMID: 15329725
  53. Rad62 protein functionally and physically associates with the smc5/smc6 protein complex and is required for chromosome integrity and recombination repair in fission yeast.
    Mol Cell Biol. 2004 Nov;24(21):9401-13 PMID: 15485909
  54. Nse1, Nse2, and a novel subunit of the Smc5-Smc6 complex, Nse3, play a crucial role in meiosis.
    Mol Biol Cell. 2004 Nov;15(11):4866-76 PMID: 15331764
  55. Molecular genetic analysis of fission yeast Schizosaccharomyces pombe.
    Methods Enzymol. 1991;194:795-823 PMID: 2005825
  56. Evolutionary conservation of excision repair in Schizosaccharomyces pombe: evidence for a family of sequences related to the Saccharomyces cerevisiae RAD2 gene.
    Nucleic Acids Res. 1993 Mar 25;21(6):1345-9 PMID: 8464724
  57. Fission yeast chk1 protein kinase links the rad checkpoint pathway to cdc2.
    Nature. 1993 May 27;363(6427):368-71 PMID: 8497322
  58. The rad16 gene of Schizosaccharomyces pombe: a homolog of the RAD1 gene of Saccharomyces cerevisiae.
    Mol Cell Biol. 1994 Mar;14(3):2029-40 PMID: 8114734
  59. Cloning and sequence analysis of rhp51+, a Schizosaccharomyces pombe homolog of the Saccharomyces cerevisiae RAD51 gene.
    Gene. 1994 May 16;142(2):207-11 PMID: 8194753
  60. Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage.
    Mol Cell Biol. 1994 Jul;14(7):4878-88 PMID: 8007985
  61. A new ATP-independent DNA endonuclease from Schizosaccharomyces pombe that recognizes cyclobutane pyrimidine dimers and 6-4 photoproducts.
    Nucleic Acids Res. 1994 Aug 11;22(15):3026-32 PMID: 8065916
  62. Cloning and characterisation of the Schizosaccharomyces pombe rad32 gene: a gene required for repair of double strand breaks and recombination.
    Nucleic Acids Res. 1995 Feb 11;23(3):383-8 PMID: 7885834
  63. rqh1+, a fission yeast gene related to the Bloom's and Werner's syndrome genes, is required for reversible S phase arrest.
    EMBO J. 1997 May 15;16(10):2682-92 PMID: 9184215
Article Info
Journal
Genetics
Abbr.
Genetics
ISSN
0016-6731
DOI
10.1534/genetics.105.044966
Published
2005-10-00
Epub
2005-00-21
Pages
457-68
Language
English
Region
United States
NLM ID
0374636
PMCID
PMC1456763
Subset
IM
Grants
NCI NIH HHS · T32 CA078207 · United States
NCI NIH HHS · CA78207 · United States
External Links
PubMed source DOI: 10.1534/genetics.105.044966 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2