SETD4-mediated KU70 methylation suppresses apoptosis

Yuan Wang, Bochao Liu, Huimei Lu, Jingmei Liu, Peter J. Romanienko, Gaetano T. Montelione, Zhiyuan Shen

Research output: Contribution to journalArticlepeer-review


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.

Original languageAmerican English
Article number110794
JournalCell Reports
Issue number6
StatePublished - May 10 2022
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


  • CP: Molecular biology
  • KU70
  • SETD4
  • apoptosis
  • lysine methylation
  • non-histone methyl-transferase


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