Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
Nucleic Acids Res. 2012 Nov;40(21):10809-20. doi: 10.1093/nar/gks862. Epub 2012 Sep 18.
Approximately 10% of all cancers, but a higher proportion of sarcomas, use the recombination-based alternative lengthening of telomeres (ALT) to maintain telomeres. Two RecQ helicase genes, BLM and WRN, play important roles in homologous recombination repair and they have been implicated in telomeric recombination activity, but their precise roles in ALT are unclear. Using analysis of sequence variation present in human telomeres, we found that a WRN- ALT+ cell line lacks the class of complex telomere mutations attributed to inter-telomeric recombination in other ALT+ cell lines. This suggests that WRN facilitates inter-telomeric recombination when there are sequence differences between the donor and recipient molecules or that sister-telomere interactions are suppressed in the presence of WRN and this promotes inter-telomeric recombination. Depleting BLM in the WRN- ALT+ cell line increased the mutation frequency at telomeres and at the MS32 minisatellite, which is a marker of ALT. The absence of complex telomere mutations persisted in BLM-depleted clones, and there was a clear increase in sequence homogenization across the telomere and MS32 repeat arrays. These data indicate that BLM suppresses unequal sister chromatid interactions that result in excessive homogenization at MS32 and at telomeres in ALT+ cells.
大约 10%的癌症，但肉瘤的比例更高，使用基于重组的端粒的替代延长（ALT）来维持端粒。两种 RecQ 解旋酶基因，BLM 和 WRN，在同源重组修复中发挥重要作用，并且它们与端粒重组活性有关，但它们在 ALT 中的精确作用尚不清楚。通过分析人类端粒中存在的序列变异，我们发现 WRN-ALT+细胞系缺乏归因于其他 ALT+细胞系中端粒间重组的复杂端粒突变类。这表明当供体和受体分子之间存在序列差异时，WRN 促进端粒间重组，或者在 WRN 存在下抑制姐妹端粒相互作用，从而促进端粒间重组。在 WRN-ALT+细胞系中耗尽 BLM 会增加端粒和 MS32 微卫星（ALT 的标志物）的突变频率。在耗尽 BLM 的克隆中，复杂的端粒突变仍然存在，并且端粒和 MS32 重复序列的序列均匀化明显增加。这些数据表明 BLM 抑制导致在 ALT+细胞中 MS32 和端粒过度均匀化的不相等姐妹染色单体相互作用。
