Chaudhary N, Nakka K K, Chavali P L, Bhat J, Chatterjee S, Chattopadhyay S
Chromatin and Disease Biology Laboratory, National Centre for Cell Science, Pune University Campus, Pune, India.
Department of Biophysics, Bose Institute, Kolkata, India.
Cell Death Dis. 2014 Oct 9;5(10):e1447. doi: 10.1038/cddis.2014.397.
Acetylation status of DNA end joining protein Ku70 dictates its function in DNA repair and Bax-mediated apoptosis. Despite the knowledge of HDACs and HATs that are reported to modulate the acetylation dynamics of Ku70, very little is known about proteins that critically coordinate these key modifications. Here, we demonstrate that nuclear matrix-associated protein scaffold/matrix-associated region-binding protein 1 (SMAR1) is a novel interacting partner of Ku70 and coordinates with HDAC6 to maintain Ku70 in a deacetylated state. Our studies revealed that knockdown of SMAR1 results in enhanced acetylation of Ku70, which leads to impaired recruitment of Ku70 in the chromatin fractions. Interestingly, ionizing radiation (IR) induces the expression of SMAR1 and its redistribution as distinct nuclear foci upon ATM-mediated phosphorylation at serine 370. Furthermore, SMAR1 regulates IR-induced G2/M cell cycle arrest by facilitating Chk2 phosphorylation. Alternatively, SMAR1 provides radioresistance by modulating the association of deacetylated Ku70 with Bax, abrogating the mitochondrial translocation of Bax. Thus, we provide mechanistic insights of SMAR1-mediated regulation of repair and apoptosis via a complex crosstalk involving Ku70, HDAC6 and Bax.
DNA 末端连接蛋白 Ku70 的乙酰化状态决定其在 DNA 修复和 Bax 介导的细胞凋亡中的功能。尽管已知有 HDACs 和 HATs 可调节 Ku70 的乙酰化动态，但对于关键协调这些关键修饰的蛋白质却知之甚少。在此，我们证明核基质相关蛋白支架/基质相关区域结合蛋白 1（SMAR1）是 Ku70 的新型相互作用伴侣，并与 HDAC6 协同作用以维持 Ku70 处于去乙酰化状态。我们的研究表明，敲低 SMAR1 会导致 Ku70 的乙酰化增强，进而导致 Ku70 在染色质组分中的募集受损。有趣的是，电离辐射（IR）诱导 SMAR1 的表达及其在 ATM 介导的丝氨酸 370 磷酸化后作为独特核灶的重新分布。此外，SMAR1 通过促进 Chk2 磷酸化来调节 IR 诱导的 G2/M 细胞周期阻滞。或者，SMAR1 通过调节去乙酰化的 Ku70 与 Bax 的关联来提供辐射抗性，从而消除 Bax 的线粒体易位。因此，我们通过涉及 Ku70、HDAC6 和 Bax 的复杂串扰，提供了 SMAR1 介导的修复和细胞凋亡调节的机制见解。
