FANCJ localization by mismatch repair is vital to maintain genomic integrity after UV irradiation.
FANCJ localization by mismatch repair is vital to maintain genomic integrity after UV irradiation.
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DOI：
10.1158/0008-5472.can-13-2474
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Cantor SB
中科院分区：
文献类型：
--
作者：
Guillemette S;Branagan A;Peng M;Dhruva A;Schärer OD;Cantor SB
核苷酸切除修复(NER)对紫外线诱导的DNA损伤的修复至关重要，但其在复制细胞中的作用尚不清楚。在这里，我们发现，包括XPF和XPG在内的NER内切酶的双重切割，促进了BRCA1和Fanconi贫血相关的DNA解旋酶FANCJ在S时相积累到紫外线诱导的损伤部位。FANCJ促进复制蛋白A的磷酸化和紫外线照射后DNA合成的停止。FANCJ相互作用缺陷突变体表明，BRCA1结合不是FANCJ定位所必需的，而与错配修复(MMR)蛋白MLH1的相互作用是必不可少的。相应地，我们发现FANCJ及其与MLH1的直接相互作用和MMR蛋白MSH2在紫外光照射下以共同的途径发挥作用。FANCJ缺陷细胞对紫外线照射的杀伤不敏感，但我们发现DNA突变显著增强。因此，我们认为FANCJ缺陷可能与皮肤癌有关。沿着这些路线，我们在黑色素瘤中发现了FANCJ的几个体细胞突变，其中一些以前在遗传性乳腺癌和Fanconi贫血中被发现。鉴于XPF突变也会导致Fanconi贫血，我们认为Fanconi贫血、NER和MMR之间的合作对于启动复制人类细胞的检查点激活以限制基因组不稳定性是必要的。
Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia–associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability.