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MutSα deficiency increases tolerance to DNA damage in yeast lacking postreplication repair.
DNA Repair ( IF 3.8 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.dnarep.2020.102870
Ingrid L Berg 1 , Jan-Olov Persson 2 , Stefan U Åström 1
Affiliation  

By combining mutations in DNA repair genes, important and unexpected interactions between different repair pathways can be discovered. In this study, we identified a novel link between mismatch repair (MMR) genes and postreplication repair (PRR) in Saccharomyces cerevisiae. Strains lacking Rad5 (HLTF in mammals), a protein important for restarting stalled replication forks in the error-free PRR pathway, were supersensitive to the DNA methylating agent methyl methanesulfonate (MMS). Deletion of the mismatch repair genes, MSH2 or MSH6, which together constitutes the MutSα complex, partially suppressed the MMS super-sensitivity of the rad5Δ strain. Deletion of MSH2 also suppressed the MMS sensitivity of mms2Δ, which acts together with Rad5 in error-free PRR. However, inactivating the mismatch repair genes MSH3 and MLH1 did not suppress rad5Δ, showing that the suppression was specific for disabling MutSα. The partial suppression did not require translesion DNA synthesis (REV1, REV3 or RAD30), base excision repair (MAG1) or homologous recombination (RAD51). Instead, the underlying mechanism was dependent on RAD52 while independent of established pathways involving RAD52, like single-strand annealing and break-induced replication. We propose a Rad5- and Rad51-independent template switch pathway, capable of compensating for the loss of the error-free template-switch subpathway of postreplication repair, triggered by the loss of MutSα.



中文翻译:

MutSα缺乏会增加缺乏复制后修复的酵母对DNA损伤的耐受性。

通过组合DNA修复基因中的突变,可以发现不同修复途径之间重要且意想不到的相互作用。在这项研究中,我们确定了酿酒酵母中错配修复(MMR)基因与复制后修复(PRR)之间的新型联系。缺乏Rad5(哺乳动物中的HLTF)的蛋白对DNA甲基化剂甲磺酸甲酯(MMS)极为敏感,该蛋白对在无错误的PRR途径中重新启动停滞的复制叉非常重要。缺失构成MusSα复合物的错配修复基因MSH2MSH6的缺失部分抑制了rad5Δ菌株的MMS超敏感性。删除MSH2还抑制了mms2Δ的MMS灵敏度,该灵敏度与Rad5一起在无差错PRR中起作用。但是,失配修复基因MSH3MLH1的失活并不能抑制rad5Δ,这表明该抑制是特定于MutSα失能的。部分抑制不需要跨病变的DNA合成(REV1 ,REV3RAD30),碱基切除修复(MAG1)或同源重组(RAD51)。相反,其潜在机制依赖于RAD52,而与涉及RAD52的既定途径无关,例如单链退火和断裂诱导的复制。我们提出了Rad5和Rad51独立的模板转换途径,能够补偿由MutSα的缺失引起的复制后修复的无错模板转换子途径的损失。

更新日期:2020-05-21
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