ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks

作者：Zha Shan; Guo Chunguang; Boboila Cristian; Oksenych Valentyn; Cheng Hwei Ling; Zhang Yu; Wesemann Duane R; Yuen Grace; Patel Harin; Goff Peter H; Dubois Richard L; Alt Frederick W^*

来源：Nature, 2011, 469(7329): 250-254.

DOI：10.1038/nature09604

Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D) J recombination DSB intermediates(1,2). The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ(3-6); however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D) J recombination(5). The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX(7). However, ATM deficiency causes only modest V(D) J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes(7-9). Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D) J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D) J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D) J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D) J recombination defects associated with marked degradation of unjoined V(D) J ends, revealing that H2AX has a role in this process.

• 出版日期2011-1-13