p53 Activity Results in DNA Replication Fork Processivity
p53 Activity Results in DNA Replication Fork Processivity
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DOI：
10.1016/j.celrep.2016.10.036
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发表时间：
2016-11-08
期刊：
影响因子：
8.8
通讯作者：
Dobbelstein, Matthias
中科院分区：
文献类型：
--
作者：
Klusmann, Ina;Rodewald, Sabrina;Dobbelstein, Matthias
p53在DNA损伤时诱导细胞死亡，但这可能并不赋予其所有的肿瘤抑制活性。我们报告说，p53激活增强DNA复制的持续合成能力，通过多标记纤维分析监测，而去除p53减少叉进展。这在肿瘤来源的U2 OS细胞中观察到，但也在杂合或纯合p53缺失的小鼠胚胎成纤维细胞中观察到，并且在具有不同p53状态的小鼠的新鲜分离的胸腺细胞中观察到。Mdm 2，一种p53诱导的基因产物，即使在p53缺陷细胞中也同样支持DNA复制，这表明持续的Mdm 2表达至少是允许p53防止复制应激的机制之一。因此，p53有助于在S期保护基因组，防止出现停滞或崩溃的复制叉。这些结果扩展了p53的肿瘤抑制功能，为事后模型（消除受损细胞）增加了事前活性;即，防止DNA在复制过程中受损。
p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. Wereport that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This is observed in tumor-derived U2OS cells but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion and in freshly isolated thymocytes frommice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supports DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53's tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity; i.e., the prevention of DNA damage during replication.