A cancer-associated DNA polymerase δ variant modeled in yeast causes a catastrophic increase in genomic instability

被引:59
|
作者
Daee, Danielle L. [1 ]
Mertz, Tony M. [1 ]
Shcherbakova, Polina V. [1 ]
机构
[1] Univ Nebraska, Eppley Inst Res Canc & Allied Dis, Med Ctr, Omaha, NE 68118 USA
基金
美国国家卫生研究院;
关键词
mutator; SNP; transient hypermutagenesis; DNA synthesis fidelity; colon cancer; CARCINOMA CELL-LINES; HUMAN TUMOR-CELLS; SACCHAROMYCES-CEREVISIAE; MUTATOR PHENOTYPE; MISMATCH REPAIR; EXONUCLEASE ACTIVITY; MUTATIONS; REPLICATION; ALPHA; GENE;
D O I
10.1073/pnas.0907526106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Accurate DNA synthesis by the replicative DNA polymerases alpha, delta, and epsilon is critical for genome stability in eukaryotes. In humans, over 20 SNPs were reported that result in amino-acid changes in Pol delta or Pol epsilon. In addition, Pol delta variants were found in colon-cancer cell lines and in sporadic colorectal carcinomas. Using the yeast-model system, we examined the functional consequences of two cancer-associated Pol delta mutations and four polymorphisms affecting well-conserved regions of Pol delta or Pol epsilon. We show that the R696W substitution in Pol delta (analog of the R689W change in the human cancer-cell line DLD-1) is lethal in haploid and homozygous diploid yeast. The cell death results from a catastrophic increase in spontaneous mutagenesis attributed to low-fidelity DNA synthesis by Pol delta-R696W. Heterozygotes survive, and the mutation rate depends on the relative expression level of wild-type versus mutant alleles. Based on these observations, we propose that the mutation rate in heterozygous human cells could be regulated by transient changes in gene expression leading to a temporary excess of Pol delta-R689W. The similarities between the mutational spectra of the yeast strains producing Pol delta-R696W and DLD-1 cells suggest that the altered Pol delta could be responsible for a significant proportion of spontaneous mutations in this cancer cell line. These results suggest that the highly error-prone Pol delta-R689W could contribute to cancer initiation and/or progression in humans.
引用
收藏
页码:157 / 162
页数:6
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