2012年9月2日 讯 /生物谷BIOON/ --一直以来，科学家都在研究为什么细胞会随着其老化而不断丧失修复自身的能力，如今来自罗彻斯特大学的研究者给出了答案，相应的研究报告刊登在了国际著名杂志Proceedings of the National Academy of Sciences上。
人类细胞中的DNA双链会进行常规地破裂以及自我修复，但是对于细胞来说，随着其不断老化，其修复系统也变得失去功能，这最终将导致组织功能的下降以及肿瘤发生率的增加。研究小组决定去探究其发生的分子机制。
研究者Seluanov和其同事发现，随着细胞老化，其修复DNA的能力下降与修复过程中所涉及的蛋白质的水平的降低同时发生。研究者通过恢复修复过程中的蛋白质水平，试图去恢复细胞修复DNA的能力，最终发现了蛋白质SIRT6在“作怪”。
在研究报告中，研究者揭示了高表达蛋白质SIRT6可以延长小鼠的寿命，而且蛋白质SIRT6可以促使DNA的高效修复。下一步，研究者计划去研究调节蛋白质SIRT6的影响因子，以更好地理解早期DNA修复的过程。
目前很多研究者都在开发激活SIRT6的药物，Seluanov教授希望他们的研究有一天会被应用于临床来延长病人的寿命以及治疗某些癌症。以前的研究表明SIRT6在修复危险类型的DNA损伤（DNA双链破裂）上扮演着重要的角色，DNA的双链断裂是非常致命的，因为其几乎不可能被修复，容易引起细胞遗传物质的重排，进而引发不可估量的后果。
细胞中存在两种修复DNA双链断裂的途径：高保真修复过程（同源重组，HR）和一种快速但极易发生错误的修复过程（非同源末端接合，NHEJ），当前的研究中揭示了由于年龄相关的HR修复功能的下降非常危险，老细胞进行高保真修复的效率比年轻细胞低38倍。研究者推测，衰老细胞或许是被迫进行NHEJ修复模式，尤其是在其老化的过程中，其修复功能会越来越低，长期如此，组织功能会严重下降，而且肿瘤发生率也会相应提高。（生物谷Bioon.com）
编译自：Researchers find a protein that helps DNA repair in aging cells
doi:10.1073/pnas.1200583109
PMC:
PMID:
Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence
Zhiyong Mao, Xiao Tian, Michael Van Meter, Zhonghe Ke, Vera Gorbunova1, and Andrei Seluanov1
Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G2/M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in “middle-aged” and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance./P>
