title: SMAR1 coordinates HDAC6-induced deacetylation of Ku70 and dictates cell fate upon irradiation.
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.
authors.affiliation: Chromatin and Disease Biology Laboratory, National Centre for Cell Science, Pune University Campus, Pune, India.
authors.forename: N
authors.initials: N
authors.lastname: Chaudhary
authors.affiliation: Chromatin and Disease Biology Laboratory, National Centre for Cell Science, Pune University Campus, Pune, India.
authors.forename: K K
authors.initials: KK
authors.lastname: Nakka
authors.affiliation: Chromatin and Disease Biology Laboratory, National Centre for Cell Science, Pune University Campus, Pune, India.
authors.forename: P L
authors.initials: PL
authors.lastname: Chavali
authors.affiliation: Department of Biophysics, Bose Institute, Kolkata, India.
authors.forename: J
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Department of Biophysics, Bose Institute, Kolkata, India.
authors.forename: S
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Chromatin and Disease Biology Laboratory, National Centre for Cell Science, Pune University Campus, Pune, India.
authors.forename: S
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002477:Cells / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004260:DNA Repair / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011839:Radiation, Ionizing; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; C417914:BANP protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051028:bcl-2-Associated X Protein; D064447:Checkpoint Kinase 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen