Inhibition of DNA recombination at telomere

Telomeres resemble double strand DNA breaks (DSBs) and, if not properly packaged and protected, are recognized by the DNA double strand break repair (DSBR) machinery. Initiation of DSB signaling at telomeres due to replicative shortening of telomeres is one of the triggers of cellular senescence, which can also be triggered by other cellular stressors, such as oxidative stress, and oncogenic signaling-induced mitotic arrest. The loss of telomere protection can result in telomere fusions via non-homologous end joining (NHEJ) of microhomology-mediated end joining (MMEJ). Loss of telomere protection accompanied by changes in the organization of telomeric chromatin (O'Sullivan et al. 2014) can trigger extension of telomeres via homologous recombination repair-mediated alternative lengthening of telomeres (ALT). ALT occurs in about 5-15% of cancers and is a telomerase-independent mechanism of replicative immortality. For review, please refer to Arnoult and Karlseder 2015 and Pickett and Reddel 2015.

端粒与双链DNA断裂（DSBs）相似，若未能得到适当的包装和保护，则会被DNA双链断裂修复（DSBR）机制所识别。端粒因复制缩短而引发的DSB信号传导的启动，是细胞衰老触发因素之一，细胞衰老亦可能由其他细胞应激源引发，例如氧化应激和由致癌信号诱导的有丝分裂阻滞。端粒保护功能的丧失可能导致端粒融合，这是通过微同源性介导的末端连接（MMEJ）的非同源末端连接（NHEJ）实现的。端粒保护功能的丧失伴随端粒染色质组织（O'Sullivan等人，2014年）的变化，可触发端粒的延伸，这是通过同源重组修复介导的替代端粒长度延伸（ALT）实现的。ALT大约发生在5-15%的癌症中，是一种端粒酶非依赖性的复制不死性机制。欲了解综述，请参阅Arnoult和Karlseder 2015年及Pickett和Reddel 2015年的著作。