SETD4-mediated KU70 methylation suppresses apoptosis

Cell Rep. 2022 May 10;39(6):110794. doi: 10.1016/j.celrep.2022.110794.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / metabolism
  • Apoptosis* / genetics
  • Cytoplasm / metabolism
  • DNA Repair*
  • Ku Autoantigen / genetics
  • Ku Autoantigen / metabolism
  • Mammals / metabolism
  • Methylation
  • Methyltransferases
  • Mice
  • Protein Processing, Post-Translational


  • Antigens, Nuclear
  • Methyltransferases
  • Setd4 protein, mouse
  • Xrcc6 protein, mouse
  • Ku Autoantigen