Global genomic instability caused by reduced expression of DNA polymerase ε in yeast.
Global genomic instability caused by reduced expression of DNA polymerase ε in yeast.
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DOI：
10.1073/pnas.2119588119
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发表时间：
2022-03-22
影响因子：
11.1
通讯作者：
Zheng DQ
中科院分区：
文献类型：
--
作者：
Zhang K;Sui Y;Li WL;Chen G;Wu XC;Kokoska RJ;Petes TD;Zheng DQ
虽然大多数基因组稳定性的遗传调控研究涉及DNA复制或DNA修复所需的基因编码序列内的突变分析，但最近在酵母中的研究表明，野生型酶水平降低也可产生突变表型。通过全基因组测序和其他方法，我们发现酵母中野生型DNA聚合酶ε水平的降低大大增加了有丝分裂重组、非整倍体和单碱基突变的速率。观察到的基因组不稳定性模式与在具有降低水平的其他复制型DNA聚合酶Pol α和Pol δ的酵母菌株中观察到的模式不同。这些观察结果与我们对癌症和其他与遗传不稳定性相关的疾病的理解有关。DNA聚合酶ε（Pol ε）是真核生物三大复制型DNA聚合酶之一。Pol ε缺陷导致基因组不稳定和多种人类疾病。在这里，我们探索了POL2（编码Pol ε催化亚基的基因）表达减少的酵母菌株中的整体基因组改变。使用全基因组SNP微阵列和测序，我们发现低水平的Pol ε使有丝分裂重组和染色体非整倍体的比率提高了两个数量级。引人注目的是，低水平的Pol ε导致核糖体DNA簇中重复序列的数量减少，并减少了端粒的长度。这些菌株也有断裂诱导复制的频率升高，导致末端杂合性丢失。此外，低水平的Pol ε通过Pol ε依赖性途径使单碱基突变率增加13倍。最后，由低水平的Pol ε引起的基因组改变的模式与在具有低水平的其他复制型DNA聚合酶Pol α和Pol δ的菌株中观察到的模式不同，这为B家族DNA聚合酶在维持基因组稳定性中的不同作用提供了进一步的见解。
Although most studies of the genetic regulation of genome stability involve an analysis of mutations within the coding sequences of genes required for DNA replication or DNA repair, recent studies in yeast show that reduced levels of wild-type enzymes can also produce a mutator phenotype. By whole-genome sequencing and other methods, we find that reduced levels of the wild-type DNA polymerase ε in yeast greatly increase the rates of mitotic recombination, aneuploidy, and single-base mutations. The observed pattern of genome instability is different from those observed in yeast strains with reduced levels of the other replicative DNA polymerases, Pol α and Pol δ. These observations are relevant to our understanding of cancer and other diseases associated with genetic instability. DNA polymerase ε (Pol ε) is one of the three replicative eukaryotic DNA polymerases. Pol ε deficiency leads to genomic instability and multiple human diseases. Here, we explored global genomic alterations in yeast strains with reduced expression of POL2, the gene that encodes the catalytic subunit of Pol ε. Using whole-genome SNP microarray and sequencing, we found that low levels of Pol ε elevated the rates of mitotic recombination and chromosomal aneuploidy by two orders of magnitude. Strikingly, low levels of Pol ε resulted in a contraction of the number of repeats in the ribosomal DNA cluster and reduced the length of telomeres. These strains also had an elevated frequency of break-induced replication, resulting in terminal loss of heterozygosity. In addition, low levels of Pol ε increased the rate of single-base mutations by 13-fold by a Pol ζ-dependent pathway. Finally, the patterns of genomic alterations caused by low levels of Pol ε were different from those observed in strains with low levels of the other replicative DNA polymerases, Pol α and Pol δ, providing further insights into the different roles of the B-family DNA polymerases in maintaining genomic stability.
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常见的与癌症相关的DNA聚合酶ε突变会导致异常强的突变器表型，表明富达缺陷与校对丧失不同。
影响因子：
11.2
作者：
Kane DP;Shcherbakova PV
通讯作者：
Shcherbakova PV
影响因子：
16.6
作者：
Garbacz MA;Lujan SA;Burkholder AB;Cox PB;Wu Q;Zhou ZX;Haber JE;Kunkel TA
通讯作者：
Kunkel TA
影响因子：
16
作者：
Bellelli R;Borel V;Logan C;Svendsen J;Cox DE;Nye E;Metcalfe K;O'Connell SM;Stamp G;Flynn HR;Snijders AP;Lassailly F;Jackson A;Boulton SJ
通讯作者：
Boulton SJ
影响因子：
64.5
作者：
Holmes, AM;Haber, JE
通讯作者：
Haber, JE
影响因子：
4.5
作者：
Lee PS;Greenwell PW;Dominska M;Gawel M;Hamilton M;Petes TD
通讯作者：
Petes TD