Zhu Xu-Dong, Niedernhofer Laura, Kuster Bernhard, Mann Matthias, Hoeijmakers Jan H J, de Lange Titia
The Rockefeller University, New York, NY 10021, USA.
Mol Cell. 2003 Dec;12(6):1489-98. doi: 10.1016/s1097-2765(03)00478-7.
Human telomeres are protected by TRF2. Inhibition of this telomeric protein results in partial loss of the telomeric 3' overhang and chromosome end fusions formed through nonhomologous end-joining (NHEJ). Here we report that ERCC1/XPF-deficient cells retained the telomeric overhang after TRF2 inhibition, identifying this nucleotide excision repair endonuclease as the culprit in overhang removal. Furthermore, these cells did not accumulate telomere fusions, suggesting that overhang processing is a prerequisite for NHEJ of telomeres. ERCC1/XPF was also identified as a component of the telomeric TRF2 complex. ERCC1/XPF-deficient mouse cells had a novel telomere phenotype, characterized by Telomeric DNA-containing Double Minute chromosomes (TDMs). We speculate that TDMs are formed through the recombination of telomeres with interstitial telomere-related sequences and that ERCC1/XPF functions to repress this process. Collectively, these data reveal an unanticipated involvement of the ERCC1/XPF NER endonuclease in the regulation of telomere integrity and establish that TRF2 prevents NHEJ at telomeres through protection of the telomeric overhang from ERCC1/XPF.
人类端粒由TRF2保护。抑制这种端粒蛋白会导致端粒3'端悬突部分丢失，并通过非同源末端连接（NHEJ）形成染色体末端融合。在此我们报告，ERCC1/XPF缺陷细胞在TRF2抑制后保留了端粒悬突，确定这种核苷酸切除修复内切核酸酶是悬突去除的罪魁祸首。此外，这些细胞没有积累端粒融合，表明悬突加工是端粒NHEJ的先决条件。ERCC1/XPF也被鉴定为端粒TRF2复合物的一个组分。ERCC1/XPF缺陷的小鼠细胞具有一种新的端粒表型，其特征为含端粒DNA的双微体染色体（TDMs）。我们推测TDMs是通过端粒与间质端粒相关序列的重组形成的，并且ERCC1/XPF的功能是抑制这一过程。总体而言，这些数据揭示了ERCC1/XPF核酸内切酶在端粒完整性调控中意想不到的作用，并证实TRF2通过保护端粒悬突免受ERCC1/XPF的影响来防止端粒处的NHEJ。
