title: Post-replication repair suppresses duplication-mediated genome instability.
abstract: RAD6 is known to suppress duplication-mediated gross chromosomal rearrangements (GCRs) but not single-copy sequence mediated GCRs. Here, we found that the RAD6- and RAD18-dependent post-replication repair (PRR) and the RAD5-, MMS2-, UBC13-dependent error-free PRR branch acted in concert with the replication stress checkpoint to suppress duplication-mediated GCRs formed by homologous recombination (HR). The Rad5 helicase activity, but not its RING finger, was required to prevent duplication-mediated GCRs, although the function of Rad5 remained dependent upon modification of PCNA at Lys164. The SRS2, SGS1, and HCS1 encoded helicases appeared to interact with Rad5, and epistasis analysis suggested that Srs2 and Hcs1 act upstream of Rad5. In contrast, Sgs1 likely functions downstream of Rad5, potentially by resolving DNA structures formed by Rad5. Our analysis is consistent with models in which PRR prevents replication damage from becoming double strand breaks (DSBs) and/or regulates the activity of HR on DSBs.
authors.affiliation: Ludwig Institute for Cancer Research, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Putnam
authors.forename: Tikvah K
authors.initials: TK
authors.lastname: Hayes
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
mesh_terms: D015825:Chromosomes, Fungal / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D015321:Gene Rearrangement; D042822:Genomic Instability; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D029701:Saccharomyces cerevisiae Proteins; C471606:RAD6 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; C076225:RAD5 protein, S cerevisiae; D004265:DNA Helicases
references.citation: Cell. 1999 Mar 5;96(5):645-53
references.pmid: 10089880
references.citation: PLoS Genet. 2010 Feb 26;6(2):e1000858
references.pmid: 20195513
references.citation: Nature. 2003 May 15;423(6937):309-12
references.pmid: 12748645
references.citation: Mol Cell Biol. 2007 Jan;27(1):102-10
references.pmid: 17060452
references.citation: J Mol Biol. 1999 Jun 4;289(2):235-48
references.pmid: 10366502
references.citation: Mol Genet Metab. 1999 Jul;67(3):183-93
references.pmid: 10381326
references.citation: Genes Dev. 2003 Jul 15;17(14):1755-67
references.pmid: 12865299
references.citation: Mol Cell Biol. 2006 Oct;26(20):7783-90
references.pmid: 16908531
references.citation: Mol Cell. 2005 Mar 4;17(5):709-20
references.pmid: 15749020
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13262-7
references.pmid: 15328403
references.citation: Nucleic Acids Res. 1997 Feb 15;25(4):743-9
references.pmid: 9016623
references.citation: Nature. 1987 Sep 10-16;329(6135):131-4
references.pmid: 3306404
references.citation: Genetics. 2006 Dec;174(4):1789-800
references.pmid: 17057245
references.citation: Methods Enzymol. 2006;409:86-100
references.pmid: 16793396
references.citation: Cell. 1994 Jan 14;76(1):145-55
references.pmid: 8287473
references.citation: Nature. 2005 Jul 21;436(7049):428-33
references.pmid: 15931174
references.citation: Mutat Res. 1981 Jun;82(1):69-85
references.pmid: 7022172
references.citation: Nat Genet. 1999 Sep;23(1):81-5
references.pmid: 10471504
references.citation: PLoS One. 2008;3(11):e3717
references.pmid: 19005567
references.citation: Genes Dev. 2005 Aug 15;19(16):1905-19
references.pmid: 16103218
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7351-5
references.pmid: 1651502
references.citation: Genome Res. 2000 May;10(5):597-610
references.pmid: 10810082
references.citation: J Biol Chem. 1997 Sep 12;272(37):23360-5
references.pmid: 9287349
references.citation: J Mol Biol. 1968 Jan 28;31(2):291-304
references.pmid: 4865486
references.citation: Genes Dev. 2005 Feb 1;19(3):339-50
references.pmid: 15687257
references.citation: J Bacteriol. 1979 Sep;139(3):866-76
references.pmid: 383698
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9747-52
references.pmid: 17535927
references.citation: Genetics. 1991 Jan;127(1):75-85
references.pmid: 1849857
references.citation: Cell. 2006 Mar 10;124(5):1069-81
references.pmid: 16487579
references.citation: Mutat Res. 1998 Mar;407(2):135-45
references.pmid: 9637242
references.citation: Mutat Res. 1976 Oct;37(1):91-110
references.pmid: 967189
references.citation: Mutat Res. 2001 Jul 12;486(2):137-46
references.pmid: 11425518
references.citation: Genetics. 1993 Jan;133(1):51-66
references.pmid: 8417989
references.citation: Nature. 2008 Dec 18;456(7224):915-20
references.pmid: 19092928
references.citation: Mol Cell Biol. 2009 Oct;29(19):5226-37
references.pmid: 19635810
references.citation: Mol Cell. 2005 Jul 1;19(1):123-33
references.pmid: 15989970
references.citation: Nucleic Acids Res. 2001 Sep 1;29(17):3487-94
references.pmid: 11522817
references.citation: Nature. 2002 Sep 12;419(6903):135-41
references.pmid: 12226657
references.citation: Mol Cell Biol. 2004 Aug;24(16):7082-90
references.pmid: 15282308
references.citation: Mol Cell Biol. 2004 May;24(10):4267-74
references.pmid: 15121847
references.citation: Mol Cell Biol. 2006 Feb;26(4):1424-33
references.pmid: 16449653
references.citation: Mol Microbiol. 2009 Jul;73(1):89-102
references.pmid: 19496932
references.citation: Curr Genet. 1990 Aug;18(2):111-6
references.pmid: 2225142
references.citation: Genetics. 1990 Apr;124(4):817-31
references.pmid: 2182387
references.citation: Genetics. 2000 Aug;155(4):1633-41
references.pmid: 10924462
references.citation: Science. 2002 Jul 26;297(5581):599-602
references.pmid: 12142537
references.citation: Cell. 1997 Jan 24;88(2):253-63
references.pmid: 9008166
references.citation: Mol Cell Biol. 2008 Sep;28(17):5432-45
references.pmid: 18591251
references.citation: J Biol Chem. 2009 Oct 23;284(43):29326-34
references.pmid: 19706603
references.citation: Nature. 2003 Sep 11;425(6954):188-91
references.pmid: 12968183
references.citation: Nucleic Acids Res. 1998 Dec 15;26(24):5589-95
references.pmid: 9837987
references.citation: Mol Cell. 2007 Oct 12;28(1):167-75
references.pmid: 17936713
references.citation: Nature. 2003 May 15;423(6937):305-9
references.pmid: 12748644
references.citation: Mol Cell Biol. 1994 Jul;14(7):4493-500
references.pmid: 8007955
references.citation: Mol Cell. 2006 Mar 3;21(5):595-604
references.pmid: 16507358
references.citation: Nature. 2000 Aug 31;406(6799):1015-9
references.pmid: 10984059
references.citation: Cell. 2008 May 16;133(4):601-11
references.pmid: 18485869
references.citation: Mol Cell. 2003 Jan;11(1):261-6
references.pmid: 12535538
references.citation: EMBO J. 2000 Jul 3;19(13):3388-97
references.pmid: 10880451
references.citation: Genetics. 1992 Nov;132(3):651-64
references.pmid: 1468624
references.citation: Mutat Res. 1998 May 25;400(1-2):45-58
references.pmid: 9685581
references.citation: Nature. 2003 Dec 18;426(6968):870-4
references.pmid: 14685245
references.citation: J Mol Biol. 1971 Oct 14;61(1):25-44
references.pmid: 4947693
references.citation: J Mol Biol. 1976 Mar 5;101(3):417-25
references.pmid: 1255724
references.citation: Biochem Biophys Res Commun. 2005 Jul 1;332(2):398-403
references.pmid: 15896708
references.citation: Nat Rev Genet. 2002 May;3(5):370-9
references.pmid: 11988762
references.citation: J Biol Chem. 2005 Mar 18;280(11):9879-86
references.pmid: 15632126
references.citation: Cell Res. 2008 Jan;18(1):162-73
references.pmid: 18157158
references.citation: Genetics. 2008 Sep;180(1):73-82
references.pmid: 18757916
references.citation: Nature. 2001 Jun 28;411(6841):1073-6
references.pmid: 11429610
references.citation: Biochemistry. 2000 Nov 28;39(47):14617-25
references.pmid: 11087418
references.citation: Nat Cell Biol. 2001 Nov;3(11):958-65
references.pmid: 11715016
references.citation: Nature. 2009 Aug 20;460(7258):984-9
references.pmid: 19641493
references.citation: Nature. 2001 Aug 2;412(6846):557-61
references.pmid: 11484058
references.citation: Mol Cell. 2008 Jul 11;31(1):57-66
references.pmid: 18614047
references.citation: DNA Repair (Amst). 2006 Dec 9;5(12):1475-88
references.pmid: 16990054
references.citation: DNA Repair (Amst). 2009 Sep 2;8(9):974-82
references.pmid: 19477695
references.citation: Biochemistry. 1997 Oct 28;36(43):13277-84
references.pmid: 9341218
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6504-8
references.pmid: 10823897
references.citation: Mol Cell Biol. 2005 Aug;25(16):7226-38
references.pmid: 16055731