2012年9月2日 訊 /生物谷BIOON/ --一直以來,，科學(xué)家都在研究為什么細(xì)胞會(huì)隨著其老化而不斷喪失修復(fù)自身的能力,，如今來自羅徹斯特大學(xué)的研究者給出了答案,，相應(yīng)的研究報(bào)告刊登在了國際著名雜志Proceedings of the National Academy of Sciences上,。
人類細(xì)胞中的DNA雙鏈會(huì)進(jìn)行常規(guī)地破裂以及自我修復(fù),，但是對(duì)于細(xì)胞來說,，隨著其不斷老化，其修復(fù)系統(tǒng)也變得失去功能,，這最終將導(dǎo)致組織功能的下降以及腫瘤發(fā)生率的增加,。研究小組決定去探究其發(fā)生的分子機(jī)制。
研究者Seluanov和其同事發(fā)現(xiàn),，隨著細(xì)胞老化,，其修復(fù)DNA的能力下降與修復(fù)過程中所涉及的蛋白質(zhì)的水平的降低同時(shí)發(fā)生。研究者通過恢復(fù)修復(fù)過程中的蛋白質(zhì)水平,，試圖去恢復(fù)細(xì)胞修復(fù)DNA的能力,，最終發(fā)現(xiàn)了蛋白質(zhì)SIRT6在“作怪”。
在研究報(bào)告中,，研究者揭示了高表達(dá)蛋白質(zhì)SIRT6可以延長小鼠的壽命,，而且蛋白質(zhì)SIRT6可以促使DNA的高效修復(fù)。下一步,，研究者計(jì)劃去研究調(diào)節(jié)蛋白質(zhì)SIRT6的影響因子,，以更好地理解早期DNA修復(fù)的過程。
目前很多研究者都在開發(fā)激活SIRT6的藥物,，Seluanov教授希望他們的研究有一天會(huì)被應(yīng)用于臨床來延長病人的壽命以及治療某些癌癥,。以前的研究表明SIRT6在修復(fù)危險(xiǎn)類型的DNA損傷（DNA雙鏈破裂）上扮演著重要的角色，DNA的雙鏈斷裂是非常致命的,，因?yàn)槠鋷缀醪豢赡鼙恍迯?fù),，容易引起細(xì)胞遺傳物質(zhì)的重排，進(jìn)而引發(fā)不可估量的后果,。
細(xì)胞中存在兩種修復(fù)DNA雙鏈斷裂的途徑：高保真修復(fù)過程（同源重組,，HR）和一種快速但極易發(fā)生錯(cuò)誤的修復(fù)過程（非同源末端接合，NHEJ）,，當(dāng)前的研究中揭示了由于年齡相關(guān)的HR修復(fù)功能的下降非常危險(xiǎn),，老細(xì)胞進(jìn)行高保真修復(fù)的效率比年輕細(xì)胞低38倍。研究者推測(cè),，衰老細(xì)胞或許是被迫進(jìn)行NHEJ修復(fù)模式,，尤其是在其老化的過程中，其修復(fù)功能會(huì)越來越低,，長期如此,，組織功能會(huì)嚴(yán)重下降，而且腫瘤發(fā)生率也會(huì)相應(yīng)提高,。（生物谷Bioon.com）
編譯自：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>
