Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system.
Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system.
复制标题
细胞凋亡触发器启动 MLL 基因内涉及非同源末端连接修复系统的易位。
作者：
C. Betti;M. Villalobos;Manuel O. Diaz;Andrew T M Vaughan
涉及MLL基因11 q23的易位是治疗相关白血病中的常见发现，并且集中在短的8.3 kb DNA片段（断点簇区域）内。此外，在经历细胞凋亡的细胞中，MLL的该区域内与外显子12相邻的特定位点被切割。我们在这里显示，使用人TK 6淋巴母细胞，辐射和凋亡触发抗CD 95抗体都能够启动易位在MLL外显子12切割位点。产生的易位连接含有与非同源末端连接（NHEJ）修复过程的操作一致的微同源区域。NHEJ过程的参与通过在凋亡裂解位点鉴定NHEJ组分DNA-PKcs来支持。磷脂酰肌醇3-激酶抑制剂渥曼青霉素对DNA-PKcs功能的抑制损害了DNA末端连接，增加了MLL内的位点特异性切割，并消除了MLL限制性易位。我们提出，单独激活凋亡效应核酸酶足以产生proleukemogenic易位，并提高了其中一些可能持续存在于逃避凋亡执行和生存的细胞的可能性。
Translocations involving the MLL gene at 11q23 are a frequent finding in therapy-related leukemia and are concentrated within a short, 8.3-kb tract of DNA, the breakpoint cluster region. In addition, a specific site adjacent to exon 12 within this region of MLL is cleaved in cells undergoing apoptosis. We show here, using human TK6 lymphoblastoid cells, that irradiation and the apoptotic trigger anti-CD95 antibody are each able to initiate translocations at the MLL exon 12 cleavage site. The translocation junctions produced contain regions of microhomology consistent with operation of the nonhomologous end joining (NHEJ) repair process. Participation of the NHEJ process is supported by the identification of the NHEJ component DNA-PKcs at the site of apoptotic cleavage. Suppression of DNA-PKcs function by the phosphatidylinositol 3-kinase inhibitor wortmannin compromises DNA end joining, increases site-specific cleavage within MLL, and eliminates MLL-restricted translocations. We propose that activation of apoptotic effector nucleases alone is sufficient to generate proleukemogenic translocations and raises the possibility that some of these may persist in cells that evade apoptotic execution and survive.
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源自共同来源的 TK6 和 WI-L2-NS 类淋巴母细胞的相对放射敏感性主要由其 p53 突变状态决定。
DOI：
10.1016/0165-7992(95)90055-1
发表时间：
1995
期刊：
Mutation research
影响因子：
--
作者：
Zhen,W;Denault,CM;Loviscek,K;Walter,S;Geng,L;Vaughan,AT
通讯作者：
Vaughan,AT
影响因子：
11.2
作者：
S. DiBiase;Z. Zeng;Richard Chen;T. Hyslop;W. Curran;G. Iliakis
通讯作者：
S. DiBiase;Z. Zeng;Richard Chen;T. Hyslop;W. Curran;G. Iliakis
影响因子：
20.3
作者：
Broeker, PLS;Super, HG;Rowley, JD
通讯作者：
Rowley, JD
影响因子：
3.4
作者：
Okayasu, R;Suetomi, K;Ullrich, RL
通讯作者：
Ullrich, RL
DOI：
10.1073/pnas.95.23.13887
发表时间：
1998-11-10
影响因子：
11.1
作者：
Boyd, KE;Wells, J;Farnham, PJ
通讯作者：
Farnham, PJ