Postreplication repair inhibits CAG•CTG repeat expansions in Saccharomyces cerevisiae

被引:49
作者
Daee, Danielle L.
Mertz, Tony
Lahue, Robert S.
机构
[1] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
[2] Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA
关键词
D O I
10.1128/MCB.01167-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Trinucleotide repeats (TNRs) are unique DNA microsatellites that can expand to cause human disease. Recently, Srs2 was identified as a protein that inhibits TNR expansions in Saccharomyces cerevisiae. Here, we demonstrate that Srs2 inhibits CAG (.) CTG expansions in conjunction with the error-free branch of postrepfication repair (PRR). Like srs2 mutants, expansions are elevated in rad18 and rad5 mutants, as well as the PRR-specific PCNA alleles pol30-K164R and pol30-K127/164R. Epistasis analysis indicates that Srs2 acts upstream of these PRR proteins. Also, like srs2 mutants, the pol30-K127/164R phenotype is specific for expansions, as this allele does not alter mutation rates at dinucleotide repeats, at nonrepeating sequences, or for CAG (.) CTG repeat contractions. Our results suggest that Srs2 action and PRR processing inhibit TNR expansions. We also investigated the relationship between PRR and Rad27 (Fen1), a well-established inhibitor of TNR expansions that acts at 5' flaps. Our results indicate that PRR protects against expansions arising from the 3' terminus, presumably replication slippage events. This work provides the first evidence that CAG (.) CTG expansions can occur by 3' slippage, and our results help define PRR as a key cellular mechanism that protects against expansions.
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页码:102 / 110
页数:9
相关论文
共 64 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
    ABOUSSEKHRA, A
    CHANET, R
    ZGAGA, Z
    CASSIERCHAUVAT, C
    HEUDE, M
    FABRE, F
    [J]. NUCLEIC ACIDS RESEARCH, 1989, 17 (18) : 7211 - 7219
  • [2] Amin NS, 1996, GENETICS, V144, P479
  • [3] Srs2 helicase of Saccharomyces cerevisiae selectively unwinds triplet repeat DNA
    Bhattacharyya, S
    Lahue, RS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (39) : 33311 - 33317
  • [4] Saccharomyces cerevisiae Srs2 DNA helicase selectively blocks expansions of trinucleotide repeats
    Bhattacharyya, S
    Lahue, RS
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (17) : 7324 - 7330
  • [5] Rad18/Rad5/Mms2-mediated polyubiquitination of PCNA is implicated in replication completion during replication stress
    Branzei, D
    Seki, M
    Enomoto, T
    [J]. GENES TO CELLS, 2004, 9 (11) : 1031 - 1042
  • [6] Suppression of genetic defects within the RAD6 pathway by srs2 is specific for error-free post-replication repair but not for damage-induced mutagenesis
    Broomfield, S
    Xiao, W
    [J]. NUCLEIC ACIDS RESEARCH, 2002, 30 (03) : 732 - 739
  • [7] DNA postreplication repair and mutagenesis in Saccharomyces cerevisiae
    Broomfield, S
    Hryciw, T
    Xiao, W
    [J]. MUTATION RESEARCH-DNA REPAIR, 2001, 486 (03): : 167 - 184
  • [8] Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion
    Campuzano, V
    Montermini, L
    Molto, MD
    Pianese, L
    Cossee, M
    Cavalcanti, F
    Monros, E
    Rodius, F
    Duclos, F
    Monticelli, A
    Zara, F
    Canizares, J
    Koutnikova, H
    Bidichandani, SI
    Gellera, C
    Brice, A
    Trouillas, P
    DeMichele, G
    Filla, A
    DeFrutos, R
    Palau, F
    Patel, PI
    DiDonato, S
    Mandel, JL
    Cocozza, S
    Koenig, M
    Pandolfo, M
    [J]. SCIENCE, 1996, 271 (5254) : 1423 - 1427
  • [9] Cejka P, 2001, GENETICS, V159, P953
  • [10] Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: Evidence from single sperm analyses
    Chong, SS
    Almqvist, E
    Telenius, H
    LaTray, L
    Nichol, K
    BourdelatParks, B
    Goldberg, YP
    Haddad, BR
    Richards, F
    Sillence, D
    Greenberg, CR
    Ives, E
    VandenEngh, G
    Hughes, MR
    Hayden, MR
    [J]. HUMAN MOLECULAR GENETICS, 1997, 6 (02) : 301 - 309