Abstract
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.
Highlights
(MARBPs) are unique class of proteins that bind to specific non-coding sequences in the genome termed as scaffold/
We explored the possibility of a DNA-mediated interaction between SMAR1 and Ku70 because both SMAR1 and Ku70 are enriched in chromatin-bound fractions upon ionizing radiation (IR)
Our findings highlight the significance of Ku70–SMAR1– HDAC6 association, which underlines an intricate crosstalk between the various regulators and eventually determines the cell fate
Summary
(MARBPs) are unique class of proteins that bind to specific non-coding sequences in the genome termed as scaffold/. Ku70 interacts and sequesters cytoplasmic pro-apoptotic protein Bax,[16,18] but the acetylation of Ku70 at its C-terminus leads to disruption of Ku70–Bax complex and mitochondrial translocation of Bax to induce apoptosis.[14,19] Positive regulation of cell survival upon stress is mediated through Ku70 deacetylation by various histone deacetylases, such as HDAC6,17,18,20 SIRT1,15 and SIRT3.21 underlying mediator/regulatory proteins that modulate the deacetylation of Ku70 in response to stress remain enigmatic. We delineated a complex molecular mechanism of DNA damage repair and cell survival upon ionizing radiation (IR)-induced cellular stress. Our study demonstrates the novel role of SMAR1 in coordinating an intricate molecular mechanism upon DNA damage through modulation of Ku70 deacetylation
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