Akhter Shamima, Legerski Randy J
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2008 Dec 5;377(1):236-41. doi: 10.1016/j.bbrc.2008.09.130. Epub 2008 Oct 9.
We have shown previously that SNM1A colocalizes with 53BP1 at sites of double-strand breaks (DSBs) induced by IR, and that these proteins interact with or without DNA damage. However, the role of SNM1A in the DNA damage response has not been elucidated. Here, we show that SNM1A is required for an efficient G1 checkpoint arrest after IR exposure. Interestingly, the localization of SNM1A to sites of DSBs does not require either 53BP1 or H2AX, nor does the localization of 53BP1 require SNM1A. However, the localization of SNM1A does require ATM. Furthermore, SNM1A is shown to be a phosphorylation substrate of ATM in vitro, and to interact with ATM in vivo particularly after exposure of cells to IR. In addition, in the absence of SNM1A the activation of the downstream ATM target p53 is reduced. These findings suggest that SNM1A acts with ATM to promote the G1 cell cycle checkpoint.
我们之前已经表明，SNM1A与53BP1在电离辐射诱导的双链断裂（DSB）位点共定位，并且这些蛋白质在有或没有DNA损伤的情况下相互作用。然而，SNM1A在DNA损伤反应中的作用尚未阐明。在此，我们表明SNM1A是电离辐射暴露后有效的G1期检查点停滞所必需的。有趣的是，SNM1A在DSB位点的定位既不需要53BP1也不需要H2AX，53BP1的定位也不需要SNM1A。然而，SNM1A的定位确实需要ATM。此外，SNM1A在体外被证明是ATM的磷酸化底物，并且在体内与ATM相互作用，特别是在细胞暴露于电离辐射后。另外，在没有SNM1A的情况下，下游ATM靶点p53的激活会降低。这些发现表明SNM1A与ATM共同作用以促进G1期细胞周期检查点。
