DNA damage checkpoints are involved in postreplication repair

被引:35
作者
Barbour, Leslie [1 ]
Ball, Lindsay G. [1 ]
Zhang, Ke [1 ]
Xiao, Wei [1 ]
机构
[1] Univ Saskatchewan, Dept Microbiol & Immunol, Saskatoon, SK S7N 5E5, Canada
关键词
D O I
10.1534/genetics.106.056283
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Saccharomyces cerevisiae MMS2 encodes a ubiquitin-conjugating enzyme variant, belongs to the error-free branch of the RAD6 postreplication repair (PRR) pathway, and is parallel to the REV3-mediated mutagenesis branch. A mutation in genes of either the MMS2 or the REV3 branch does not result in extreme sensitivity to DNA-damaging agents; however, deletion of both subpathways of PRR results in a synergistic phenotype. Nevertheless, the double Mutant is not as sensitive to DNA-damaging agents as a rad6 or rad18 mutant defective in the entire PRR pathway, suggesting the presence of an additional subpathway within PRR. A synthetic lethal screen was employed in the presence of a sublethal dose of a DNA-damaging agent to identify novel genes involved in PRR, which resulted in the isolation of RAD9 as a candidate PRR gene. Epistatic analysis showed that rad9 is synergistic to both mms2 and rev3 with respect to killing by methyl methane-sulfortate (MMS), and the triple mutant is nearly as sensitive as the rad18 single mutant. In addition, rad9 rad18 is no more sensitive to MMS than the rad18 single mutant, suggesting that rad9 plays a role within the PRR pathway. Moreover, deletion of RAD9 reduces damage-induced mutagenesis and the mms2 spontaneous and induced mutagenesis is partially dependent on the RAD9 gene. We further demonstrated that the observed synergistic interactions apply to any two members between different branches of PRR and G(I)/S and G(2)/M checkpoint genes. These results Suggest that a damage checkpoint is essential for tolerance mediated by both the error-free and error prone branches of PRR.
引用
收藏
页码:1789 / 1800
页数:12
相关论文
共 72 条
[1]   RADH, A GENE OF SACCHAROMYCES-CEREVISIAE ENCODING A PUTATIVE DNA HELICASE INVOLVED IN DNA-REPAIR - CHARACTERISTICS OF RADH MUTANTS AND SEQUENCE OF THE GENE [J].
ABOUSSEKHRA, A ;
CHANET, R ;
ZGAGA, Z ;
CASSIERCHAUVAT, C ;
HEUDE, M ;
FABRE, F .
NUCLEIC ACIDS RESEARCH, 1989, 17 (18) :7211-7219
[2]   Cell cycle checkpoint signaling through the ATM and ATR kinases [J].
Abraham, RT .
GENES & DEVELOPMENT, 2001, 15 (17) :2177-2196
[3]  
[Anonymous], 2005, DNA REPAIR MUTAGENES
[4]   Improving synthetic lethal screens by regulating the yeast centromere sequence [J].
Barbour, L ;
Zhu, Y ;
Xiao, W .
GENOME, 2000, 43 (05) :910-917
[5]   Regulation of alternative replication bypass pathways at stalled replication forks and its effects on genome stability: a yeast model [J].
Barbour, L ;
Xiao, W .
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2003, 532 (1-2) :137-155
[6]  
Barrington RA, 1999, J IMMUNOL, V162, P911
[7]   MMS2, encoding a ubiquitin-conjugating-enzyme-like protein, is a member of the yeast error-free postreplication repair pathway [J].
Broomfield, S ;
Chow, BL ;
Xiao, W .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (10) :5678-5683
[8]   DNA postreplication repair and mutagenesis in Saccharomyces cerevisiae [J].
Broomfield, S ;
Hryciw, T ;
Xiao, W .
MUTATION RESEARCH-DNA REPAIR, 2001, 486 (03) :167-184
[9]   RAD9 and RAD24 define two additive, interacting branches of the DNA damage checkpoint pathway in budding yeast normally required for Rad53 modification and activation [J].
de la Torre-Ruiz, MA ;
Green, CM ;
Lowndes, NF .
EMBO JOURNAL, 1998, 17 (09) :2687-2698
[10]   Cell cycle checkpoints: Preventing an identity crisis [J].
Elledge, SJ .
SCIENCE, 1996, 274 (5293) :1664-1672