The 3′-flap endonuclease XPF-ERCC1 promotes alternative end joining and chromosomal translocation during B cell class switching
The 3′-flap endonuclease XPF-ERCC1 promotes alternative end joining and chromosomal translocation during B cell class switching
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DOI：
10.1016/j.celrep.2021.109756
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发表时间：
2021-09-29
期刊：
影响因子：
8.8
通讯作者：
Dong, Junchao
中科院分区：
文献类型：
--
作者：
Bai, Wanyu;Zhu, Guangchao;Dong, Junchao
经典非同源末端连接（c-NHEJ）缺陷鼠细胞中的稳健替代末端连接（A-EJ）特征在于双链断裂（DSB）末端切除和微同源性（MH）使用，并促进染色体易位。负责在A-EJ中切除和MH退火后去除3'单链突出端的活性仍不清楚。我们表明，在成熟小鼠B细胞中的类别转换重组（CSR）过程中，结构特异性核酸内切酶复合物XPF-ERCC 1 SLX 4虽然不是正常CSR所必需的，但代表了A-EJ介导的CSR的核苷酸切除修复独立的3'瓣去除活性。DNA连接酶4和XPF-ERCC 1缺陷的B细胞表现出进一步受损的类别转换，减少与切除的S区DSB的连接，而不改变S-S连接中的MH模式。在ERCC 1缺陷型A-EJ细胞中，主要在细胞周期的S/G2期产生的3'单链DNA（ssDNA）瓣对核酸酶拆分敏感。此外，ERCC 1促进Lig 4（-/-）细胞中的c-myc-IgH易位。我们的研究揭示了活瓣核酸内切酶XPF-ERCC 1在小鼠B细胞A-EJ和致癌易位中的重要作用。
Robust alternative end joining (A-EJ) in classical non-homologous end joining (c-NHEJ)-deficient murine cells features double-strand break (DSB) end resection and microhomology (MH) usage and promotes chromosomal translocation. The activities responsible for removing 3' single-strand overhangs following resection and MH annealing in A-EJ remain unclear. We show that, during class switch recombination (CSR) in mature mouse B cells, the structure-specific endonuclease complex XPF-ERCC1SLX4, although not required for normal CSR, represents a nucleotide-excision-repair-independent 3' flap removal activity for A-EJ-mediated CSR. B cells deficient in DNA ligase 4 and XPF-ERCC1 exhibit further impaired class switching, reducing joining to the resected S region DSBs without altering the MH pattern in S-S junctions. In ERCC1-deficient A-EJ cells, 3' single-stranded DNA (ssDNA) flaps that are generated predominantly in S/G2 phase of the cell cycle are susceptible to nuclease resolution. Moreover, ERCC1 promotes c-myc-IgH translocation in Lig4(-/-) cells. Our study reveals an important role of the flap endonuclease XPF-ERCC1 in A-EJ and oncogenic translocation in mouse B cells.