Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.
Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.
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DOI：
10.1136/jmedgenet-2016-103847
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发表时间：
2016-10
影响因子：
4
通讯作者：
Andreassen PR
中科院分区：
文献类型：
--
作者：
Park JY;Virts EL;Jankowska A;Wiek C;Othman M;Chakraborty SC;Vance GH;Alkuraya FS;Hanenberg H;Andreassen PR
范可尼贫血（FA）是一种异质性遗传性疾病，临床特征为进行性骨髓衰竭、先天性异常和易患恶性肿瘤。根据细胞表型校正，确定XRCC2是否为FA基因。来自先前鉴定的XRCC2双等位基因突变患者的细胞（900677）在其他突变中与野生型XRCC2进行遗传补充。野生型XRCC2可以纠正FA细胞的三种表型特征，这些表型特征都与DNA链间交联的修复有关，包括对丝裂霉素C （MMC）的敏感性增加、染色体断裂和细胞周期中G2-M的积累。此外，患者携带的XRCC2 p.R215X突变体是不稳定的。这为该突变的发病机制提供了解释，900677细胞中XRCC2-RAD51B-C-D复合物中其他蛋白质的水平降低也提供了解释。在900677细胞中，FANCD2单泛素化和病灶形成是正常的，而RAD51病灶的组装则不正常。因此，900677细胞对电离辐射的超敏反应也表明，XRCC2在FA-BRCA通路中起作用较晚。与其他FA细胞相比，这些细胞对奥拉帕尼和甲醛的敏感性较低。XRCC2/FANCU是一个FA基因，另一个RAD51平行基因RAD51C/FANCO也是一个FA基因。值得注意的是，与FANCD2下游的FA基因子集类似，XRCC2/FANCU的双等位基因突变与骨髓衰竭无关。综上所述，我们的结果对FA及其遗传起源相关的表型产生了重要的见解。
Fanconi anemia (FA) is a heterogeneous inherited disorder clinically characterized by progressive bone marrow failure, congenital anomalies, and a predisposition to malignancies. Determine, based on correction of cellular phenotypes, whether XRCC2 is a FA gene. Cells (900677) from a previously identified patient with biallelic mutation of XRCC2, among other mutations, were genetically complemented with wild-type XRCC2. Wild-type XRCC2 corrects each of three phenotypes characteristic of FA cells, all related to the repair of DNA interstrand crosslinks, including increased sensitivity to mitomycin C (MMC), chromosome breakage, and G2-M accumulation in the cell cycle. Further, the p.R215X mutant of XRCC2, which is harbored by the patient, is unstable. This provides an explanation for the pathogenesis of this mutant, as does the fact that 900677 cells have reduced levels of other proteins in the XRCC2-RAD51B-C-D complex. Also, FANCD2 monoubiquitination and foci formation, but not assembly of RAD51 foci, are normal in 900677 cells. Thus, XRCC2 acts late in the FA-BRCA pathway as also suggested by hypersensitivity of 900677 cells to ionizing radiation. These cells also share milder sensitivities toward olaparib and formaldehyde with certain other FA cells. XRCC2/FANCU is a FA gene, as is another RAD51 paralog gene, RAD51C/FANCO. Notably, similar to a subset of FA genes that act downstream of FANCD2, biallelic mutation of XRCC2/FANCU has not been associated with bone marrow failure. Taken together, our results yield important insights into phenotypes related to FA and its genetic origins.
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通讯作者：
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