PDF(Pubmed)
Abstract：
In order to avoid replicative senescence, tumor cells must acquire a telomere maintenance mechanism. Beside telomerase activation, a minority of tumors employs a recombinational mechanism called Alternative Lengthening of Telomeres (ALT). Several studies have investigated the potential ALT stimulation by inactivation of ATRX in tumor cells, obtaining contrasting results. Differently, since ALT can be viewed as a mechanism to overcome telomere shortening-mediated replicative senescence, we have investigated the effects of the inhibition of ATRX and p53 in aging primary fibroblasts. We observed that senescence leads to a phenotype that seems permissive for ALT activity, i.e. high levels of ALT-associated PML bodies (APB), telomeric damage and telomeric cohesion. On the other hand, RAD51 is highly repressed and thus telomeric recombination, upon which the ALT machinery relies, is almost absent. Silencing of ATRX greatly increases telomeric recombination in young cells, but is not able to overcome senescence-induced repression of homologous recombination. Conversely, inhibition of both p53 and ATRX leads to a phenotype reminiscent of some aspects of ALT activity, with a further increase of APB, a decrease of telomere shortening (and increased proliferation) and, above all, an increase of telomeric recombination.
摘要：
为了避免复制性衰老，肿瘤细胞必须获得端粒维持机制。除了端粒酶激活，少数肿瘤采用称为端粒选择性延长(ALT)的重组机制。一些研究已经调查了肿瘤细胞中ATRX失活的潜在ALT刺激，获得对比结果。不同的是,由于ALT可以被视为克服端粒缩短介导的复制衰老的机制，我们研究了ATRX和p53在衰老的原代成纤维细胞中的抑制作用。我们观察到衰老导致似乎允许ALT活性的表型，即高水平的ALT相关PML体（APB），端粒损伤和端粒内聚。另一方面,RAD51被高度抑制，因此端粒重组，ALT机械所依赖的，几乎缺席。ATRX的沉默大大增加了年轻细胞中的端粒重组，但不能克服衰老诱导的同源重组抑制。相反，抑制p53和ATRX导致的表型让人想起ALT活性的某些方面，随着APB的进一步增加，端粒缩短（和增殖增加）减少，最重要的是,端粒重组的增加。
