Hyper telomere recombination accelerates replicative senescence and may promote premature aging
Hyper telomere recombination accelerates replicative senescence and may promote premature aging
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DOI：
10.1073/pnas.1006338107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Bailey, Susan M.
中科院分区：
文献类型：
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作者：
Hagelstrom, R. Tanner;Blagoev, Krastan B.;Bailey, Susan M.
Werner综合征和Bloom综合征分别由RecQ解旋酶Werner(WRN)和Bloom(BLM)缺陷引起，并表现出过早衰老的表型。类似地，XFE孕激素综合征是由ERCC1-XPF DNA修复内切酶缺陷引起的。为了深入了解细胞衰老和人类衰老的起源，我们分析了WRN、BLM或ERCC1-XPF缺陷的原代人成纤维细胞中姐妹染色单体交换(SCE)频率与位置[即基因组(G-SCE)与端粒(T-SCE)DNA]的相关性。与我们的其他研究一致，我们发现在端粒酶阴性而不是端粒酶阳性背景下T-SCE升高的证据。在端粒酶阴性的WRN缺陷细胞中，T-姐妹染色单体交换频率显著高于对照组，而G-姐妹染色单体交换频率无显著差异。相反，无论基因组位置如何，BLM缺陷细胞的姐妹染色单体交换频率都显著升高。在ERCC1-XPF缺陷细胞中，T-或G-姐妹染色单体交换频率与对照组无差异。一个理论模型被开发出来，它允许对T-SCE频率增加的细胞后果进行电子计算机研究。该模型预测，在T-SCE增加的细胞中，即使端粒丢失的平均速度没有改变，复制衰老的开始也会显著加快。在端粒酶缺陷细胞中，细胞过早衰老可能是一种强大的肿瘤抑制机制，突变会导致T-SCE水平上升。此外，T-SCE驱动的细胞过早衰老可能是Werner和Bloom综合征加速衰老的一个因素，但不是XFE孕激素综合征。
Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE-but not G-SCE-frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.