Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Nat Cell Biol. 2011 Aug 21;13(9):1139-45. doi: 10.1038/ncb2326.
Loss of telomere protection causes natural chromosome ends to become recognized by DNA-damage response and repair proteins. These events result in ligation of chromosome ends with dysfunctional telomeres, thereby causing chromosomal aberrations on cell division. The control of these potentially dangerous events at deprotected chromosome ends with their unique telomeric chromatin configuration is poorly understood. In particular, it is unknown to what extent bulky modification of telomeric chromatin is involved. Here we show that uncapped telomeres accumulate ubiquitylated histone H2A in a manner dependent on the E3 ligase RNF8. The ability of RNF8 to ubiquitylate telomeric chromatin is associated with its capacity to facilitate accumulation of both 53BP1 and phospho-ATM at uncapped telomeres and to promote non-homologous end-joining of deprotected chromosome ends. In line with the detrimental effect of RNF8 on uncapped telomeres, depletion of RNF8, as well as of the E3 ligase RNF168, reduces telomere-induced genome instability. This indicates that, besides suppressing tumorigenesis by mediating repair of DNA double-strand breaks, RNF8 and RNF168 might enhance cancer development by aggravating telomere-induced genome instability.
端粒保护的丧失导致天然染色体末端被 DNA 损伤反应和修复蛋白识别。这些事件导致染色体末端与功能失调的端粒连接，从而导致细胞分裂中的染色体异常。对于这些具有独特端粒染色质结构的无保护染色体末端的潜在危险事件的控制知之甚少。特别是，尚不清楚端粒染色质的大量修饰在何种程度上涉及其中。在这里，我们表明未封闭的端粒以依赖于 E3 连接酶 RNF8 的方式积累泛素化组蛋白 H2A。RNF8 对端粒染色质进行泛素化的能力与其促进 53BP1 和磷酸化 ATM 在未封闭端粒处积累的能力以及促进去保护染色体末端的非同源末端连接相关。与 RNF8 对未封闭端粒的有害影响一致，RNF8 和 E3 连接酶 RNF168 的耗竭均减少了端粒诱导的基因组不稳定性。这表明，RNF8 和 RNF168 除了通过介导 DNA 双链断裂修复来抑制肿瘤发生外，还可能通过加剧端粒诱导的基因组不稳定性来促进癌症发展。
