Functional interplay between BRCA2/FancD1 and FancC in DNA repair
Functional interplay between BRCA2/FancD1 and FancC in DNA repair
复制标题
DOI：
10.1074/jbc.m603290200
复制
发表时间：
2006-07-28
影响因子：
4.8
通讯作者：
Takata, Minoru
中科院分区：
文献类型：
--
作者：
Kitao, Hiroyuki;Yamamoto, Kazuhiko;Takata, Minoru
一种罕见的遗传性疾病，范可尼贫血（FA），是由一系列基因突变引起的，这些基因在一个共同的FA通路/网络中相互作用。这些基因编码FA“核心”复合物的成分、关键因子FancD 2、家族性乳腺癌抑制因子BRCA 2/FancD 1和Brip 1/FancJ解旋酶。虽然已知BRCA 2通过调节Rad 51重组酶在同源重组修复中发挥关键作用，但BRCA 2与其他FA基因之间的确切功能关系尚不清楚。在这里，我们表明，BRCA 2依赖性染色质负载的Rad 51丝裂霉素C治疗后，不受破坏的FANCC或FANCD 2。Rad 51和FancD 2形成相互独立的共定位亚核灶。此外，我们创建了一个条件性BRCA 2截短突变缺乏C-末端保守结构域（CTD）（brca 2 Δ CTD），并在此背景下破坏FANCC基因。fancc/brca 2 Delta CTD双突变体揭示了FANCC和BRCA 2 CTD在X射线敏感性方面的上位关系。与此相反，顺铂敏感性和丝裂霉素C诱导的染色体畸变水平增加fancc/brca 2 δ CTD细胞相对于任何一个单一的突变。综上所述，这些结果表明，FA蛋白与BRCA 2/Rad 51介导的同源重组在双链断裂修复中一起工作，而FA途径在链间交联修复中起着独立于BRCA 2 CTD的作用。这些结果提供了对经典FA通路和BRCA 2之间的功能相互作用的见解。
A rare hereditary disorder, Fanconi anemia (FA), is caused by mutations in an array of genes, which interact in a common FA pathway/network. These genes encode components of the FA "core" complex, a key factor FancD2, the familial breast cancer suppressor BRCA2/FancD1, and Brip1/FancJ helicase. Although BRCA2 is known to play a pivotal role in homologous recombination repair by regulating Rad51 recombinase, the precise functional relationship between BRCA2 and the other FA genes is unclear. Here we show that BRCA2-dependent chromatin loading of Rad51 after mitomycin C treatment was not compromised by disruption of FANCC or FANCD2. Rad51 and FancD2 form co-localizing subnuclear foci independently of each other. Furthermore, we created a conditional BRCA2 truncating mutation lacking the C-terminal conserved domain (CTD) (brca2 Delta CTD), and disrupted the FANCC gene in this background. The fancc/brca2 Delta CTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity. In contrast, levels of cisplatin sensitivity and mitomycin C-induced chromosomal aberrations were increased in fancc/brca2 Delta CTD cells relative to either single mutant. Taken together, these results indicate that FA proteins work together with BRCA2/Rad51-mediated homologous recombination in double strand break repair, whereas the FA pathway plays a role that is independent of the CTD of BRCA2 in interstrand cross-link repair. These results provide insights into the functional interplay between the classical FA pathway and BRCA2.