Minter-Dykhouse Katherine, Ward Irene, Huen Michael S Y, Chen Junjie, Lou Zhenkun
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
J Cell Biol. 2008 Jun 2;181(5):727-35. doi: 10.1083/jcb.200801083. Epub 2008 May 26.
The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.
DNA损伤反应（DDR）通路在发育、基因组稳定性和肿瘤抑制中的重要性已得到充分认可。尽管53BP1和MDC1最近被确定为细胞对DNA双链断裂反应中的关键上游介质，但它们在共济失调毛细血管扩张症突变（ATM）信号级联反应中的相对层级仍存在争议。为了研究MDC1和53BP1在ATM反应通路中的不同功能以及潜在的重叠功能，我们构建了这两个基因均缺失的小鼠。出乎意料的是，与单独缺失MDC1相比，同时缺失MDC1和53BP1既没有显著增加DDR缺陷的严重程度，也没有增加肿瘤发生率。我们还表明，MDC1在DNA损伤反应中调节53BP1焦点的形成和磷酸化。这些结果表明，MDC1在DDR通路和肿瘤抑制中作为53BP1的上游调节因子发挥作用。
