Ploidy dictates repair pathway choice under DNA replication stress.
This study reports an unusual ploidy-specific response to replication stress presented by a defective minichromosome maintenance (MCM) helicase allele in yeast. The corresponding mouse allele, Mcm4(Chaos3), predisposes mice to mammary gland tumors. While mcm4(Chaos3) causes replication stress in both haploid and diploid yeast, only diploid mutants exhibit G2/M delay, severe genetic instability (GIN), and reduced viability. These different outcomes are associated with distinct repair pathways adopted in haploid and diploid mutants. Haploid mutants use the Rad6-dependent pathways that resume stalled forks, whereas the diploid mutants use the Rad52- and MRX-dependent pathways that repair double strand breaks. The repair pathway choice is irreversible and not regulated by the availability of repair enzymes. This ploidy effect is independent of mating type heterozygosity and not further enhanced by increasing ploidy. In summary, a defective MCM helicase causes GIN only in particular cell types. In response to replication stress, early events associated with ploidy dictate the repair pathway choice. This study uncovers a fundamental difference between haplophase and diplophase in the maintenance of genome integrity.
Department of Molecular Biology and Genetics, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853, USA.
Xin Chenglin
XC
Li
Bik K
BK
Tye
D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004261:DNA Replication; D004271:DNA, Fungal / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004171:Diploidy; D056426:Genetic Loci; D006238:Haploidy; D006579:Heterozygote; D064148:Minichromosome Maintenance Complex Component 4; D009154:Mutation; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; C471606:RAD6 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; D051135:Rad51 Recombinase; D004265:DNA Helicases; C092802:MCM4 protein, S cerevisiae; D064148:Minichromosome Maintenance Complex Component 4
Genetics. 1996 Mar;142(3):749-59
8849885
Nat Genet. 2000 Jun;25(2):192-4
10835635
Nat Genet. 2007 Jan;39(1):93-8
17143284
Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404
10357855
Cell Cycle. 2007 May 15;6(10):1135-40
17495541
Mol Microbiol. 2008 Sep;69(5):1246-54
18627461
Cell. 1997 Oct 3;91(1):59-69
9335335
Nature. 2009 May 21;459(7245):460-3
19357644
Genetics. 1968 May;59(1):33-6
5683638
Mutat Res. 1993 Dec;290(2):239-47
7694115
Mol Cell. 2008 Jul 25;31(2):287-93
18657510
Mol Cell. 2007 Oct 12;28(1):134-46
17936710
Oncogene. 2007 Nov 29;26(54):7601-6
17563742
Mol Cell Biol. 2005 Aug;25(16):7158-69
16055725
Nature. 2008 Oct 9;455(7214):770-4
18806779
PLoS Biol. 2010 Nov 02;8(11):e1000523
21072241
PLoS Genet. 2007 Aug;3(8):e134
17696614
Cell Res. 2008 Jan;18(1):134-47
18157161
Genetics. 1985 Jul;110(3):381-95
3894160
PLoS Biol. 2004 May;2(5):E110
15138496
Mutat Res. 1980 Dec;73(2):251-65
7007877
Mol Microbiol. 2006 Jan;59(2):637-50
16390456
Genes Dev. 2001 Nov 15;15(22):3005-12
11711435
Mol Cell Biol. 1997 May;17(5):2851-8
9111357
Mol Cell Biol. 2000 Oct;20(20):7490-504
11003646
Cell Cycle. 2008 Sep 15;7(18):2902-6
18769152
Cell. 1999 May 28;97(5):621-33
10367891
Genetics. 2006 Sep;174(1):41-55
16782999
Nature. 2003 Aug 28;424(6952):1078-83
12944972
Mutat Res. 2003 Nov 27;532(1-2):137-55
14643434
Nature. 2008 Oct 30;455(7217):1251-4
18820680
Science. 1999 Jul 9;285(5425):251-4
10398601
PLoS Biol. 2009 Jul;7(7):e1000161
19636358
Heredity (Edinb). 2009 Jan;102(1):24-30
18766201
Mol Cell Biol. 2004 Aug;24(16):7082-90
15282308
J Genet. 1949 Dec;49(3):264-85
24536673
Genes Dev. 2009 Feb 1;23(3):291-303
19204116
Nature. 2001 Dec 6;414(6864):666-9
11740566
EMBO J. 1998 Sep 15;17(18):5497-508
9736627
EMBO J. 2000 Jul 3;19(13):3388-97
10880451
Curr Opin Cell Biol. 2005 Dec;17(6):568-75
16226452
Science. 2008 Mar 7;319(5868):1352-5
18323444
Nat Cell Biol. 2007 May;9(5):493-505
17450133
Nature. 2006 Oct 5;443(7111):541-7
17024086
Nat Cell Biol. 2001 Jul;3(7):619-27
11433293
Genetics. 1993 Mar;133(3):489-98
8454201