Panda Suchismita, Isbatan Ayman, Adami Guy R
Department of Oral Medicine and Diagnostic Sciences, Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, United States.
Mech Ageing Dev. 2008 Jun;129(6):332-40. doi: 10.1016/j.mad.2008.02.014. Epub 2008 Mar 14.
The cellular DNA damage response (DDR) entails the activation of ATM, ATR and/or DNA PK protein kinases that causes modifications of proteins including Chk1, Chk2 and 53BP1, aggregation of DDR proteins into foci, and activation of p53. The DDR is thought to be required for initiation and maintenance of cellular senescence. Potentially senescent cells with DNA damage foci occur in large numbers in vivo with many diseases, but, with the exception of mammalian dermis, there is little evidence for that with normal aging. After experimental induction of cellular senescence in the livers of juvenile mice, there was robust expression of DDR markers in hepatocytes at 1 week; however, by 7 weeks, activation of ATM/ATR kinase targets was limited, although cells with DNA damage foci were present. An analysis of hepatocytes of aged, 22-month-old mice, not experimentally exposed to genotoxins, showed limited activation of ATM/ATR targets, though high numbers of cells with DNA damage foci were found, similar to that seen many weeks after artificial senescence induction in young mice. Based on senescence heterochromatin and SA ss Gal assays of the 22-month-old mouse liver, more than 20% of hepatocytes were potentially senescent, though only some components of the DDR were enriched.
细胞DNA损伤反应（DDR）需要激活ATM、ATR和/或DNA PK蛋白激酶，这些激酶会导致包括Chk1、Chk2和53BP1在内的蛋白质发生修饰，DDR蛋白聚集形成病灶，并激活p53。DDR被认为是细胞衰老起始和维持所必需的。体内许多疾病中存在大量带有DNA损伤病灶的潜在衰老细胞，但除了哺乳动物真皮外，几乎没有证据表明正常衰老过程中存在这种情况。在幼年小鼠肝脏中实验性诱导细胞衰老后，第1周时肝细胞中DDR标志物有强烈表达；然而，到第7周时，尽管存在带有DNA损伤病灶的细胞，但ATM/ATR激酶靶点的激活受到限制。对未经过实验性暴露于基因毒素的22月龄老年小鼠肝细胞的分析显示，ATM/ATR靶点的激活有限，尽管发现大量带有DNA损伤病灶的细胞，这与在幼年小鼠中人工诱导衰老数周后所见情况相似。基于对22月龄小鼠肝脏的衰老异染色质和SA-β-Gal检测，超过20%的肝细胞可能处于衰老状态，尽管DDR的某些成分有所富集。
