The Protexin complex counters resection on stalled forks to promote homologous recombination and crosslink repair.
The Protexin complex counters resection on stalled forks to promote homologous recombination and crosslink repair.
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DOI：
10.1016/j.molcel.2021.09.008
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发表时间：
2021-11-04
期刊：
影响因子：
16
通讯作者：
Elledge SJ
中科院分区：
文献类型：
--
作者：
Adeyemi RO;Willis NA;Elia AEH;Clairmont C;Li S;Wu X;D'Andrea AD;Scully R;Elledge SJ
保护停滞的复制叉子对基因组的稳定性至关重要。通过遗传和蛋白质组学分析，我们发现了含有单链DNA结合蛋白SCAI和DNA聚合酶Rev3的Protex in复合体。Protex in特别用于保护因核苷酸耗尽、分叉障碍、脆弱部位和DNA链间交联(ICL)而停滞不前的分叉，在这些分叉中，Protex in促进同源重组和修复。蛋白原丢失导致单链DNA积聚和严重的基因组不稳定响应ICLS。Protex in与RNAPOL2相互作用，两者都反对ExO1‘S切除由FANCM转位酶活性重塑的叉子上的DNA。该通路独立于BRCA/RAD51介导的分叉稳定，BRCA2突变的细胞依赖SCAI生存。这些数据表明，Protex in及其相关因子建立了一种新的分叉保护途径，该途径部分通过依赖Rev3聚合酶的摘除DNA的重新合成机制来抵消分叉切除，特别是在ICL停滞的分叉上。Adeyemi等人。进行了全基因组范围的顺铂敏感性筛查并鉴定了SCAI，这表明它们对于在复制应激后维持基因组稳定性非常重要。他们表明，SCAI与一种名为Protex in的聚合酶Rev3形成了复合体。Protex in通过保护复制叉免受核酸酶的影响，在受损后保持DNA的完整性。
Protection of stalled replication forks is critical to genomic stability. Using genetic and proteomic analyses we discovered the Protexin complex containing the ssDNA binding protein SCAI and the DNA polymerase REV3. Protexin is required specifically for protecting forks stalled by nucleotide depletion, fork barriers, fragile sites and DNA interstrand crosslinks (ICLs) where it promotes homologous recombination and repair. Protexin loss leads to ssDNA accumulation and profound genomic instability in response to ICLs. Protexin interacts with RNA POL2 and both oppose EXO1’s resection of DNA on forks remodeled by the FANCM translocase activity. This pathway acts independently of BRCA/RAD51-mediated fork stabilization, and cells with BRCA2 mutations were dependent on SCAI for survival. These data suggest that Protexin and its associated factors establish a new fork protection pathway that counteracts fork resection in part through a REV3 polymerase-dependent resynthesis mechanism of excised DNA, particularly at ICL stalled forks. Adeyemi et al. performed genome-wide cisplatin sensitivity screens and identified SCAI, which they show to be important for maintaining genome stability following replication stress. They show SCAI is in complex with a polymerase, REV3, which they term Protexin. Protexin maintains DNA integrity after damage by protecting replication forks from nucleases.
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影响因子：
4.5
作者：
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通讯作者：
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DOI：
10.1083/jcb.202101092
发表时间：
2021-09-06
期刊：
The Journal of cell biology
影响因子：
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影响因子：
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影响因子：
16
作者：
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