Cohesin Is Limiting for the Suppression of DNA Damage–Induced Recombination between Homologous Chromosomes
Double-strand break (DSB) repair through homologous recombination (HR) is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin) is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage–induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G2/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G2/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage–induced recombinants in G2/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer.
Vyšlo v časopise:
Cohesin Is Limiting for the Suppression of DNA Damage–Induced Recombination between Homologous Chromosomes. PLoS Genet 6(7): e32767. doi:10.1371/journal.pgen.1001006
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001006
Souhrn
Double-strand break (DSB) repair through homologous recombination (HR) is an evolutionarily conserved process that is generally error-free. The risk to genome stability posed by nonallelic recombination or loss-of-heterozygosity could be reduced by confining HR to sister chromatids, thereby preventing recombination between homologous chromosomes. Here we show that the sister chromatid cohesion complex (cohesin) is a limiting factor in the control of DSB repair and genome stability and that it suppresses DNA damage–induced interactions between homologues. We developed a gene dosage system in tetraploid yeast to address limitations on various essential components in DSB repair and HR. Unlike RAD50 and RAD51, which play a direct role in HR, a 4-fold reduction in the number of essential MCD1 sister chromatid cohesion subunit genes affected survival of gamma-irradiated G2/M cells. The decreased survival reflected a reduction in DSB repair. Importantly, HR between homologous chromosomes was strongly increased by ionizing radiation in G2/M cells with a single copy of MCD1 or SMC3 even at radiation doses where survival was high and DSB repair was efficient. The increased recombination also extended to nonlethal doses of UV, which did not induce DSBs. The DNA damage–induced recombinants in G2/M cells included crossovers. Thus, the cohesin complex has a dual role in protecting chromosome integrity: it promotes DSB repair and recombination between sister chromatids, and it suppresses damage-induced recombination between homologues. The effects of limited amounts of Mcd1and Smc3 indicate that small changes in cohesin levels may increase the risk of genome instability, which may lead to genetic diseases and cancer.
Zdroje
1. GhaemmaghamiS
HuhWK
BowerK
HowsonRW
BelleA
2003 Global analysis of protein expression in yeast. Nature 425 737 741
2. SigalA
MiloR
CohenA
Geva-ZatorskyN
KleinY
2006 Variability and memory of protein levels in human cells. Nature 444 643 646
3. SigalA
MiloR
CohenA
Geva-ZatorskyN
KleinY
2006 Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins. Nat Methods 3 525 531
4. JinYH
ClarkAB
SlebosRJ
Al-RefaiH
TaylorJA
2003 Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34 326 329
5. PardoB
Gomez-GonzalezB
AguileraA
2009 DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci 66 1039 1056
6. ArguesoJL
WestmorelandJ
MieczkowskiPA
GawelM
PetesTD
2008 Double-strand breaks associated with repetitive DNA can reshape the genome. Proc Natl Acad Sci U S A 105 11845 11850
7. RichardsonC
JasinM
2000 Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405 697 700
8. TischfieldJA
1997 Loss of heterozygosity or: how I learned to stop worrying and love mitotic recombination. Am J Hum Genet 61 995 999
9. GuW
ZhangF
LupskiJR
2008 Mechanisms for human genomic rearrangements. Pathogenetics 1 4
10. HanK
LeeJ
MeyerTJ
RemediosP
GoodwinL
2008 L1 recombination-associated deletions generate human genomic variation. Proc Natl Acad Sci U S A 105 19366 19371
11. JasinM
2002 Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21 8981 8993
12. StromeED
WuX
KimmelM
PlonSE
2008 Heterozygous screen in Saccharomyces cerevisiae identifies dosage-sensitive genes that affect chromosome stability. Genetics 178 1193 1207
13. DurantST
NickoloffJA
2005 Good timing in the cell cycle for precise DNA repair by BRCA1. Cell Cycle 4 1216 1222
14. DateO
KatsuraM
IshidaM
YoshiharaT
KinomuraA
2006 Haploinsufficiency of RAD51B causes centrosome fragmentation and aneuploidy in human cells. Cancer Res 66 6018 6024
15. ResnickMA
SetlowJK
1972 Photoreactivation and gene dosage in yeast. J Bacteriol 109 1307 1309
16. HoKS
1975 The gene dosage effect of the rad52 mutation on X-ray survival curves of tetraploid yeast strains. Mutat Res 33 165 172
17. ResnickMA
1975 The repair of double-strand breaks in chromosomal DNA of yeast. Basic Life Sci 5B 549 556
18. WestmorelandJ
MaW
YanY
Van HulleK
MalkovaA
2009 RAD50 Is Required for Efficient Initiation of Resection and Recombinational Repair at Random, gamma-Induced Double-Strand Break Ends. PLoS Genet 5 e1000656 doi:10.1371/journal.pgen.1000656
19. MimitouEP
SymingtonLS
2009 DNA end resection: many nucleases make light work. DNA Repair (Amst) 8 983 995
20. San FilippoJ
SungP
KleinH
2008 Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 77 229 257
21. SugawaraN
WangX
HaberJE
2003 In vivo roles of Rad52, Rad54, and Rad55 proteins in Rad51-mediated recombination. Mol Cell 12 209 219
22. UnalE
Arbel-EdenA
SattlerU
ShroffR
LichtenM
2004 DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol Cell 16 991 1002
23. SjogrenC
NasmythK
2001 Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol 11 991 995
24. OnnI
Heidinger-PauliJM
GuacciV
UnalE
KoshlandDE
2008 Sister chromatid cohesion: a simple concept with a complex reality. Annu Rev Cell Dev Biol 24 105 129
25. StromL
LindroosHB
ShirahigeK
SjogrenC
2004 Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol Cell 16 1003 1015
26. StromL
KarlssonC
LindroosHB
WedahlS
KatouY
2007 Postreplicative formation of cohesion is required for repair and induced by a single DNA break. Science 317 242 245
27. UnalE
Heidinger-PauliJM
KoshlandD
2007 DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science 317 245 248
28. KadykLC
HartwellLH
1992 Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics 132 387 402
29. Cortes-LedesmaF
AguileraA
2006 Double-strand breaks arising by replication through a nick are repaired by cohesin-dependent sister-chromatid exchange. EMBO Rep 7 919 926
30. ResnickMA
MartinP
1976 The repair of double-strand breaks in the nuclear DNA of Saccharomyces cerevisiae and its genetic control. Mol Gen Genet 143 119 129
31. GuacciV
KoshlandD
StrunnikovA
1997 A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell 91 47 57
32. StorchovaZ
BrenemanA
CandeJ
DunnJ
BurbankK
2006 Genome-wide genetic analysis of polyploidy in yeast. Nature 443 541 547
33. GalliA
SchiestlRH
1995 On the mechanism of UV and gamma-ray-induced intrachromosomal recombination in yeast cells synchronized in different stages of the cell cycle. Mol Gen Genet 248 301 310
34. GalliA
SchiestlRH
1996 Hydroxyurea induces recombination in dividing but not in G1 or G2 cell cycle arrested yeast cells. Mutat Res 354 69 75
35. LeePS
GreenwellPW
DominskaM
GawelM
HamiltonM
2009 A fine-structure map of spontaneous mitotic crossovers in the yeast Saccharomyces cerevisiae. PLoS Genet 5 e1000410 doi:10.1371/journal.pgen.1000410
36. IvanovEL
SugawaraN
WhiteCI
FabreF
HaberJE
1994 Mutations in XRS2 and RAD50 delay but do not prevent mating-type switching in Saccharomyces cerevisiae. Mol Cell Biol 14 3414 3425
37. GlynnEF
MegeePC
YuHG
MistrotC
UnalE
2004 Genome-wide mapping of the cohesin complex in the yeast Saccharomyces cerevisiae. PLoS Biol 2 e259 doi:10.1371/journal.pbio.0020259
38. BlatY
KlecknerN
1999 Cohesins bind to preferential sites along yeast chromosome III, with differential regulation along arms versus the centric region. Cell 98 249 259
39. RowlandBD
RoigMB
NishinoT
KurzeA
UluocakP
2009 Building sister chromatid cohesion: smc3 acetylation counteracts an antiestablishment activity. Mol Cell 33 763 774
40. SutaniT
KawaguchiT
KannoR
ItohT
ShirahigeK
2009 Budding yeast Wpl1(Rad61)-Pds5 complex counteracts sister chromatid cohesion-establishing reaction. Curr Biol 19 492 497
41. ResnickMA
1978 Similar responses to ionizing radiation of fungal and vertebrate cells and the importance of DNA doublestrand breaks. J Theor Biol 71 339 346
42. LettierG
FengQ
de MayoloAA
ErdenizN
ReidRJ
2006 The role of DNA double-strand breaks in spontaneous homologous recombination in S. cerevisiae. PLoS Genet 2 e194 10.1371/journal.pgen.0020194
43. PfanderB
MoldovanGL
SacherM
HoegeC
JentschS
2005 SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436 428 433
44. BauerschmidtC
ArrichielloC
Burdak-RothkammS
WoodcockM
HillMA
2010 Cohesin promotes the repair of ionizing radiation-induced DNA double-strand breaks in replicated chromatin. Nucleic Acids Res 38 477 487
45. KimJS
KrasievaTB
LaMorteV
TaylorAM
YokomoriK
2002 Specific recruitment of human cohesin to laser-induced DNA damage. J Biol Chem 277 45149 45153
46. KimST
XuB
KastanMB
2002 Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev 16 560 570
47. ZhangJ
ShiX
LiY
KimBJ
JiaJ
2008 Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Mol Cell 31 143 151
48. UnalE
Heidinger-PauliJM
KimW
GuacciV
OnnI
2008 A molecular determinant for the establishment of sister chromatid cohesion. Science 321 566 569
49. BarberTD
McManusK
YuenKW
ReisM
ParmigianiG
2008 Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci U S A 105 3443 3448
50. OttoSP
2007 The evolutionary consequences of polyploidy. Cell 131 452 462
51. GuidottiJE
BregerieO
RobertA
DebeyP
BrechotC
2003 Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem 278 19095 19101
52. GanemNJ
StorchovaZ
PellmanD
2007 Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17 157 162
53. ZhangF
GuW
HurlesME
LupskiJR
2009 Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10 451 481
54. TranHT
KeenJD
KrickerM
ResnickMA
GordeninDA
1997 Hypermutability of homonucleotide runs in mismatch repair and DNA polymerase proofreading yeast mutants. Mol Cell Biol 17 2859 2865
55. StoriciF
ResnickMA
2006 The delitto perfetto approach to in vivo site-directed mutagenesis and chromosome rearrangements with synthetic oligonucleotides in yeast. Methods Enzymol 409 329 345
56. BennettCB
LewisAL
BaldwinKK
ResnickMA
1993 Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proc Natl Acad Sci U S A 90 5613 5617
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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