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SMC5/6 acts jointly with Fanconi anemia factors to support DNA repair and genome stability.
EMBO Reports ( IF 6.5 ) Pub Date : 2019-12-23 , DOI: 10.15252/embr.201948222
Francesco Rossi 1 , Anne Helbling-Leclerc 2 , Ryotaro Kawasumi 1 , Nanda Kumar Jegadesan 1 , Xinlin Xu 3 , Pierre Devulder 2 , Takuya Abe 1 , Minoru Takata 4 , Dongyi Xu 3 , Filippo Rosselli 2 , Dana Branzei 1, 5
Affiliation  

SMC5/6 function in genome integrity remains elusive. Here, we show that SMC5 dysfunction in avian DT40 B cells causes mitotic delay and hypersensitivity toward DNA intra- and inter-strand crosslinkers (ICLs), with smc5 mutants being epistatic to FANCC and FANCM mutations affecting the Fanconi anemia (FA) pathway. Mutations in the checkpoint clamp loader RAD17 and the DNA helicase DDX11, acting in an FA-like pathway, do not aggravate the damage sensitivity caused by SMC5 dysfunction in DT40 cells. SMC5/6 knockdown in HeLa cells causes MMC sensitivity, increases nuclear bridges, micronuclei, and mitotic catastrophes in a manner similar and non-additive to FANCD2 knockdown. In both DT40 and HeLa systems, SMC5/6 deficiency does not affect FANCD2 ubiquitylation and, unlike FANCD2 depletion, RAD51 focus formation. SMC5/6 components further physically interact with FANCD2-I in human cells. Altogether, our data suggest that SMC5/6 functions jointly with the FA pathway to support genome integrity and DNA repair and may be implicated in FA or FA-related human disorders.

中文翻译:

SMC5/6 与 Fanconi 贫血因子共同作用,支持 DNA 修复和基因组稳定性。

SMC5/6 在基因组完整性中的功能仍然难以捉摸。在这里,我们发现禽类 DT40 B 细胞中的 SMC5 功能障碍会导致有丝分裂延迟和对 DNA 链内和链间交联剂 (ICL) 的过敏,其中 smc5 突变体上位于影响范可尼贫血 (FA) 途径的 FANCC 和 FANCM 突变。检查点夹钳加载器 RAD17 和 DNA 解旋酶 DDX11 的突变以 FA 样途径起作用,不会加重 DT40 细胞中 SMC5 功能障碍引起的损伤敏感性。HeLa 细胞中的 SMC5/6 敲低会导致 MMC 敏感性,增加核桥、微核和有丝分裂灾难,其方式与 FANCD2 敲低类似且不相加。在 DT40 和 HeLa 系统中,SMC5/6 缺陷不会影响 FANCD2 泛素化,并且与 FANCD2 耗竭不同的是,RAD51 焦点形成。SMC5/6 成分进一步与人类细胞中的 FANCD2-I 发生物理相互作用。总而言之,我们的数据表明 SMC5/6 与 FA 通路共同发挥作用,支持基因组完整性和 DNA 修复,并可能与 FA 或 FA 相关的人类疾病有关。
更新日期:2020-02-06
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