Howard Hughes Medical Institute and School of Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2013 May 17;8(5):e59986. doi: 10.1371/journal.pone.0059986. Print 2013.
Checkpoint kinase 2 (Chk2) is a major regulator of DNA damage response and can induce alternative cellular responses: cell cycle arrest and DNA repair or programmed cell death. Here, we report the identification of a new role of Chk2 in transcriptional regulation that also contributes to modulating the balance between survival and apoptosis following DNA damage. We found that Chk2 interacts with members of the NCoR/SMRT transcriptional co-regulator complexes and serves as a functional component of the repressor complex, being required for recruitment of SMRT on the promoter of pro-apoptotic genes upon DNA damage. Thus, the co-repressor SMRT exerts a critical protective action against genotoxic stress-induced caspase activation, repressing a functionally important cohort of pro-apoptotic genes. Amongst them, SMRT is responsible for basal repression of Wip1, a phosphatase that de-phosphorylates and inactivates Chk2, thus affecting a feedback loop responsible for licensing the correct timing of Chk2 activation and the proper execution of the DNA repair process.
细胞周期检测点激酶 2（Chk2）是 DNA 损伤反应的主要调节因子，可诱导细胞的替代反应：细胞周期阻滞和 DNA 修复或程序性细胞死亡。在这里，我们报告了 Chk2 在转录调节中的一个新作用，它也有助于调节 DNA 损伤后存活和细胞凋亡之间的平衡。我们发现 Chk2 与 NCoR/SMRT 转录共调节因子复合物的成员相互作用，并作为抑制复合物的功能成分，在 DNA 损伤后，招募 SMRT 到促凋亡基因的启动子上。因此，共抑制因子 SMRT 对细胞毒性应激诱导的半胱天冬酶激活具有重要的保护作用，抑制了一组具有重要功能的促凋亡基因。其中，SMRT 负责基础抑制磷酸酶 Wip1，Wip1 去磷酸化并失活 Chk2，从而影响反馈环，负责许可 Chk2 激活的正确时机和 DNA 修复过程的正确执行。
