Genome-wide contributions of the MutSα- and MutSβ-dependent DNA mismatch repair pathways to the maintenance of genetic stability in Saccharomyces cerevisiae.
Genome-wide contributions of the MutSα- and MutSβ-dependent DNA mismatch repair pathways to the maintenance of genetic stability in Saccharomyces cerevisiae.
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DOI：
10.1016/j.jbc.2023.104705
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Kadyrov, Farid A.
中科院分区：
文献类型：
--
作者：
Kadyrova, Lyudmila Y.;Mieczkowski, Piotr A.;Kadyrov, Farid A.
DNA错配修复（MMR）系统是抑制人类遗传性和散发性癌症的主要DNA修复系统。在真核生物中，MutSα依赖性和MutSβ依赖性MMR途径纠正DNA聚合酶错误。在这里，我们研究了这两个途径在酿酒酵母的全基因组水平。我们发现，MutSα依赖性MMR的失活使全基因组突变率增加了10.17倍，MutSβ依赖性MMR的缺失使全基因组突变率增加了10.4倍。我们还发现，MutSα依赖性MMR没有显示出保护编码或非编码DNA免受突变的偏好，而MutSβ依赖性MMR优先保护非编码DNA免受突变。msh 6 Δ菌株中最常见的突变是C>T转换，而1-至6-bp缺失是msh 3 Δ菌株中最常见的遗传改变。值得注意的是，MutSα依赖性MMR比MutSβ依赖性MMR更重要地保护免受1-bp插入，而MutSβ依赖性MMR在防御1-bp缺失和2-至6-bp indel中具有更关键的作用。我们还确定酵母MSH 6缺失的突变特征与人类MMR缺陷的突变特征相似。此外，我们的分析表明，与其他5′-NCN-3′三核苷酸相比，5′-GCA-3′三核苷酸在msh 6 Δ细胞的中心位置积累C>T转换的风险最高，并且在−1位置存在G/A碱基对于C>T转换的有效MutSα依赖性抑制非常重要。我们的研究结果突出了MutSα依赖性和MutSβ依赖性MMR通路的作用之间的关键差异。
The DNA mismatch repair (MMR) system is a major DNA repair system that suppresses both inherited and sporadic cancers in humans. In eukaryotes, the MutSα-dependent and MutSβ-dependent MMR pathways correct DNA polymerase errors. Here, we investigated these two pathways on a whole genome level in Saccharomyces cerevisiae. We found that inactivation of MutSα-dependent MMR increases the genome-wide mutation rate by ∼17-fold and loss of MutSβ-dependent MMR elevates the genome-wide mutation rate by ∼4-fold. We also found that MutSα-dependent MMR does not show a preference for protecting coding or noncoding DNA from mutations, whereas MutSβ-dependent MMR preferentially protects noncoding DNA from mutations. The most frequent mutations in the msh6Δ strain are C>T transitions, whereas 1- to 6-bp deletions are the most common genetic alterations in the msh3Δ strain. Strikingly, MutSα-dependent MMR is more important than MutSβ-dependent MMR for protection from 1-bp insertions, while MutSβ-dependent MMR has a more critical role in the defense against 1-bp deletions and 2- to 6-bp indels. We also determined that a mutational signature of yeast MSH6 loss is similar to mutational signatures of human MMR deficiency. Furthermore, our analysis showed that compared to other 5′-NCN-3′ trinucleotides, 5′-GCA-3′ trinucleotides are at the highest risk of accumulating C>T transitions at the central position in the msh6Δ cells and that the presence of a G/A base at the −1 position is important for the efficient MutSα-dependent suppression of C>T transitions. Our results highlight key differences between the roles of the MutSα-dependent and MutSβ-dependent MMR pathways.
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影响因子：
16
作者：
Ghodgaonkar, Medini Manohar;Lazzaro, Federico;Olivera-Pimentel, Maite;Artola-Boran, Mariela;Cejka, Petr;Reijns, Martin A.;Jackson, Andrew P.;Plevani, Paolo;Muzi-Falconi, Marco;Jiricny, Josef
通讯作者：
Jiricny, Josef
影响因子：
4.5
作者：
Dahal BK;Kadyrova LY;Delfino KR;Rogozin IB;Gujar V;Lobachev KS;Kadyrov FA
通讯作者：
Kadyrov FA
影响因子：
56.9
作者：
DRUMMOND, JT;LI, GM;MODRICH, P
通讯作者：
MODRICH, P
影响因子：
4.8
作者：
Blanko, Elena Rodriges;Kadyrova, Lyudmila Y.;Kadyrov, Farid A.
通讯作者：
Kadyrov, Farid A.
影响因子：
4.8
作者：
Genschel, J;Bazemore, LR;Modrich, P
通讯作者：
Modrich, P