@article{71a76b1a3b9245ab94cdf7de9808c23c,
title = "SETD4-mediated KU70 methylation suppresses apoptosis",
abstract = "The mammalian KU70 is a pleiotropic protein functioning in DNA repair and cytoplasmic suppression of apoptosis. We report a regulatory mechanism by which KU70's cytoplasmic function is enabled due to a methylation at K570 of KU70 by SET-domain-containing protein 4 (SETD4). While SETD4 silencing reduces the level of methylated KU70, over-expression of SETD4 enhances methylation of KU70. Mutations of Y272 and Y284 of SETD4 abrogate methylation of KU70. Although SETD4 is predominantly a nuclear protein, the methylated KU70 is enriched in the cytoplasm. SETD4 knockdown enhances staurosporine (STS)-induced apoptosis and cell killing. Over-expression of the wild-type (WT) SETD4, but not the SETD4-Y272/Y284F mutant, suppresses STS-induced apoptosis. The KU70-K570R (mouse Ku70-K568R) mutation dampens the anti-apoptosis activity of KU70. Our study identifies KU70 as a non-histone substrate of SETD4, discovers a post-translational modification of KU70, and uncovers a role for SETD4 and KU70-K570 methylation in the suppression of apoptosis.",
keywords = "CP: Molecular biology, KU70, SETD4, apoptosis, lysine methylation, non-histone methyl-transferase",
author = "Yuan Wang and Bochao Liu and Huimei Lu and Jingmei Liu and Romanienko, {Peter J.} and Montelione, {Gaetano T.} and Zhiyuan Shen",
note = "Funding Information: This research was supported by NIH R01CA195612 , NIH R01CA260724 , NIH P01CA250957 , and NJCCR DCHS20CRF002 to Z.S., by NJCCR DCHS19PPC011 to Y.W., by NIH R35GM141818 to G.T.M., and by the Genome Editing Shared Resources of The Rutgers Cancer Institute of New Jersey ( P30CA072720 ). Z.S. acknowledges the support of the Robert Wood Johnson Foundation to the Rutgers Cancer Institute of New Jersey. We thank Drs. Shijie Lan and Yanying Huo for assistance at the early stage of this study and Dr. Rongjin Guan for assistance on structural modeling. Funding Information: This research was supported by NIH R01CA195612, NIH R01CA260724, NIH P01CA250957, and NJCCR DCHS20CRF002 to Z.S. by NJCCR DCHS19PPC011 to Y.W. by NIH R35GM141818 to G.T.M. and by the Genome Editing Shared Resources of The Rutgers Cancer Institute of New Jersey (P30CA072720). Z.S. acknowledges the support of the Robert Wood Johnson Foundation to the Rutgers Cancer Institute of New Jersey. We thank Drs. Shijie Lan and Yanying Huo for assistance at the early stage of this study and Dr. Rongjin Guan for assistance on structural modeling. Y.W. and Z.S. designed the experiments, performed data analysis, and drafted the initial version of manuscript. Y.W. B.L. H.L. J.L. and P.J.R. performed experiments. G.T.M. provided computational structural analysis. G.T.M. and P.J.R. provided revisions in the final draft of the manuscript. Z.S. directed and oversaw the project, secured funding for the study, and completed the final version of the manuscript. G.T.M. is a founder of the Nexomics Biosciences, and this affiliation presents no competing interests with respect to this study. The authors declare that there were no other competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = may,
day = "10",
doi = "https://doi.org/10.1016/j.celrep.2022.110794",
language = "American English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}