Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.
Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.
复制标题
Snm1B/Apollo 在范可尼贫血途径中响应 DNA 链间交联发挥作用。
DOI：
10.1093/hmg/ddr153
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发表时间：
2011
影响因子：
3.5
通讯作者：
Sekiguchi,JoAnnM
中科院分区：
文献类型：
--
作者：
Mason,JenniferM;Sekiguchi,JoAnnM
范可尼贫血（FA）是一种遗传性染色体不稳定性疾病，以儿童再生障碍性贫血、发育异常和癌症易感性为特征。FA的标志性表型之一是细胞对诱导DNA链间交联（ICL）的药物（如丝裂霉素C（MMC））的超敏反应。FA是由至少14个基因突变引起的，这些基因在复制过程中对ICL的消退起作用。FA蛋白在蛋白质网络的背景下与在不同途径中起作用的多种修复因子协调作用。SNM 1B/Apollo是金属β-内酰胺酶/β-CASP核酸酶家族的成员，已被证明在ICL修复中发挥作用。然而，SNM 1B和FA蛋白网络之间的关系尚不清楚。在目前的研究中，我们建立了SNM 1B功能上位中央FA因子，FANCD 2，在ICL损伤和同源定向修复DNA双链断裂后的细胞存活。我们还证明，MMC诱导的染色体异常增加SNM 1B-耗尽的细胞，这种表型是不是进一步加剧后，无论是FANCD 2或另一个关键FA蛋白，FANCI耗尽。此外，我们发现SNM 1B是必需的适当本地化的关键修复因子，包括FANCD 2，BRCA 1和RAD 51，MMC诱导的亚核灶。我们的研究结果表明，SNM 1B功能在FA通路ICL损伤的修复。
Fanconi anemia (FA) is an inherited chromosomal instability disorder characterized by childhood aplastic anemia, developmental abnormalities and cancer predisposition. One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC). FA is caused by mutation in at least 14 genes which function in the resolution of ICLs during replication. The FA proteins act within the context of a protein network in coordination with multiple repair factors that function in distinct pathways. SNM1B/Apollo is a member of metallo-β-lactamase/βCASP family of nucleases and has been demonstrated to function in ICL repair. However, the relationship between SNM1B and the FA protein network is not known. In the current study, we establish that SNM1B functions epistatically to the central FA factor, FANCD2, in cellular survival after ICL damage and homology-directed repair of DNA double-strand breaks. We also demonstrate that MMC-induced chromosomal anomalies are increased in SNM1B-depleted cells, and this phenotype is not further exacerbated upon depletion of either FANCD2 or another key FA protein, FANCI. Furthermore, we find that SNM1B is required for proper localization of critical repair factors, including FANCD2, BRCA1 and RAD51, to MMC-induced subnuclear foci. Our findings demonstrate that SNM1B functions within the FA pathway during the repair of ICL damage.