The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.
The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.
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DOI：
10.1073/pnas.2201738119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
Li, Guo-Min
中科院分区：
文献类型：
--
作者：
Zhang, Junqiu;Zhao, Xin;Liu, Lu;Li, Hao-Dong;Gu, Liya;Castrillon, Diego H.;Li, Guo-Min
DNA错配修复（MMR）因其通过纠正复制过程中产生的错对来维持复制保真度而闻名。在这里，我们发现了一种不寻常的MMR功能，在复制应激反应中促进基因组不稳定。在复制胁迫下，错配识别蛋白MutSα与复制叉的结合阻止了叉保护因子FANCD2和BRCA1装载到复制叉上，并促进外切酶MRE11招募到DNA上进行新生链降解。这种依赖于muts α的mre11催化的DNA降解导致DNA断裂和染色体异常，从而导致超突变表型。错配修复（Mismatch repair， MMR）是一种复制耦合DNA修复机制，在复制叉上起着多重作用。公认的MMR功能包括纠正逃避DNA聚合酶校对活性的错合并核苷酸，识别非错配的DNA加合物，并触发DNA损伤反应。为了确定MMR是否在表达一种超变异DNA聚合酶（Pol]）的细胞中调节复制进程，该酶携带氨基酸286 （Pol] -P286R）上的脯氨酸-精氨酸取代，我们发现了一种不寻常的MMR功能，以响应羟基脲（HU）诱导的复制应激。羟基脲处理的Pol -P286R细胞表现出mre11催化的新生链降解增加。MRE11的这种降解依赖于错配识别蛋白MutSα及其与停滞复制叉的结合。MutSα在复制叉上结合的增加也与复制叉保护因子FANCD2和BRCA1的装载减少有关，这表明MutSα阻断了这些叉保护因子装载到复制叉上的过程。我们发现muts α依赖的mre11催化叉降解诱导DNA断裂和各种染色体异常。因此，与众所周知的确保复制保真度的MMR功能不同，新发现的促进基因组不稳定性的MMR活性也可能通过消除流氓细胞在癌症预防中发挥作用。
DNA mismatch repair (MMR) is well known for its role in maintaining replication fidelity by correcting mispairs generated during replication. Here, we identify an unusual MMR function to promote genome instability in the replication stress response. Under replication stress, binding of the mismatch recognition protein MutSα to replication forks blocks the loading of fork protection factors FANCD2 and BRCA1 to replication forks and promotes the recruitment of exonuclease MRE11 onto DNA to nascent strand degradation. This MutSα-dependent MRE11-catalyzed DNA degradation causes DNA breaks and chromosome abnormalities, contributing to an ultramutator phenotype. Mismatch repair (MMR) is a replication-coupled DNA repair mechanism and plays multiple roles at the replication fork. The well-established MMR functions include correcting misincorporated nucleotides that have escaped the proofreading activity of DNA polymerases, recognizing nonmismatched DNA adducts, and triggering a DNA damage response. In an attempt to determine whether MMR regulates replication progression in cells expressing an ultramutable DNA polymerase ɛ (Polɛ), carrying a proline-to-arginine substitution at amino acid 286 (Polɛ-P286R), we identified an unusual MMR function in response to hydroxyurea (HU)-induced replication stress. Polɛ-P286R cells treated with hydroxyurea exhibit increased MRE11-catalyzed nascent strand degradation. This degradation by MRE11 depends on the mismatch recognition protein MutSα and its binding to stalled replication forks. Increased MutSα binding at replication forks is also associated with decreased loading of replication fork protection factors FANCD2 and BRCA1, suggesting blockage of these fork protection factors from loading to replication forks by MutSα. We find that the MutSα-dependent MRE11-catalyzed fork degradation induces DNA breaks and various chromosome abnormalities. Therefore, unlike the well-known MMR functions of ensuring replication fidelity, the newly identified MMR activity of promoting genome instability may also play a role in cancer avoidance by eliminating rogue cells.
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影响因子：
16
作者：
Kim JJ;Lee SY;Choi JH;Woo HG;Xhemalce B;Miller KM
通讯作者：
Miller KM
DOI：
10.1016/bs.enz.2016.03.003
发表时间：
2016
期刊：
The Enzymes
影响因子：
--
作者：
Boehm EM;Gildenberg MS;Washington MT
通讯作者：
Washington MT
DOI：
10.1007/978-1-4939-1680-1_10
发表时间：
2015
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dungrawala, Huzefa;Cortez, David
通讯作者：
Cortez, David
影响因子：
11.4
作者：
Ammazzalorso, Francesca;Pirzio, Livia Maria;Pichierri, Pietro
通讯作者：
Pichierri, Pietro
DOI：
10.1073/pnas.1911310116
发表时间：
2019-12-17
影响因子：
11.1
作者：
Cuevas, Ileana C.;Sahoo, Subhransu S.;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.