Mutations in yeast replication proteins that increase CAG/CTG expansions also increase repeat fragility

被引:85
作者
Callahan, JL
Andrews, KJ
Zakian, VA
Freudenreich, CH
机构
[1] Tufts Univ, Dept Biol, Medford, MA 02155 USA
[2] Tufts Univ, Genet Program, Medford, MA 02155 USA
[3] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
关键词
D O I
10.1128/MCB.23.21.7849-7860.2003
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
Expansion of trinucleotide repeats (TNRs) is the causative mutation in several human genetic diseases. Expanded TNR tracts are both unstable (changing in length) and fragile (displaying an increased propensity to break). We have investigated the relationship between fidelity of lagging-strand replication and both stability and fragility of TNRs. We devised a new yeast artificial chromomosme (YAC)-based assay for chromosome breakage to analyze fragility of CAG/CTG tracts in mutants deficient for proteins involved in lagging-strand replication: Fen1/Rad27, an endo/exonuclease involved in Okazaki fragment maturation, the nuclease/helicase Dna2, RNase HI, DNA ligase, polymerase delta, and primase. We found that deletion of RAD27 caused a large increase in breakage of short and long CAG/CTG tracts, and defects in DNA ligase and primase increased breakage of long tracts. We also found a correlation between mutations that increase CAG/CTG tract breakage and those that increase repeat expansion. These results suggest that processes that generate strand breaks, such as faulty Okazaki fragment processing or DNA repair, are an important source of TNR expansions.
引用
收藏
页码:7849 / 7860
页数:12
相关论文
共 93 条
[21]   INTER-NUCLEAR TRANSFER OF GENETIC INFORMATION IN KAR1-1-KAR1 HETEROKARYONS IN SACCHAROMYCES CEREVISIAE [J].
DUTCHER, SK .
MOLECULAR AND CELLULAR BIOLOGY, 1981, 1 (03) :245-253
[22]   MUTATIONS IN CONSERVED YEAST DNA PRIMASE DOMAINS IMPAIR DNA-REPLICATION INVIVO [J].
FRANCESCONI, S ;
LONGHESE, MP ;
PISERI, A ;
SANTOCANALE, C ;
LUCCHINI, G ;
PLEVANI, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (09) :3877-3881
[23]   Yeast RNase H(35) is the counterpart of the mammalian RNase HI, and is evolutionarily related to prokaryotic RNase HII [J].
Frank, P ;
Braunshofer-Reiter, C ;
Wintersberger, U .
FEBS LETTERS, 1998, 421 (01) :23-26
[24]   Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome [J].
Freudenreich, CH ;
Stavenhagen, JB ;
Zakian, VA .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (04) :2090-2098
[25]   Expansion and length-dependent fragility of CTG repeats in yeast [J].
Freudenreich, CH ;
Kantrow, SM ;
Zakian, VA .
SCIENCE, 1998, 279 (5352) :853-856
[26]  
GACY AM, 1995, CELL, V81, P533
[27]  
Gary R, 1999, MOL CELL BIOL, V19, P5373
[28]   Repeat expansion - All in a flap? [J].
Gordenin, DA ;
Kunkel, TA ;
Resnick, MA .
NATURE GENETICS, 1997, 16 (02) :116-118
[29]   Weak strand displacement activity enables human DNA polymerase β to expand CAG/CTG triplet repeats at strand breaks [J].
Hartenstine, MJ ;
Goodman, MF ;
Petruska, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (44) :41379-41389
[30]  
HARTWELL LH, 1973, GENETICS, V74, P267