DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation

J Biol Chem. 2012 Aug 31;287(36):30789-99. doi: 10.1074/jbc.M112.390120. Epub 2012 Jul 23.

Abstract

Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a nucleocytoplasmic shuttling protein that is a key player in the p53-triggered DNA damage response, acting as a cofactor for p53 in response to DNA damage. hnRNP K is a substrate of the ubiquitin E3 ligase MDM2 and, upon DNA damage, is de-ubiquitylated. In sharp contrast with the role and consequences of the other post-translational modifications, nothing is known about the role of SUMO conjugation to hnRNP K in p53 transcriptional co-activation. In the present work, we show that hnRNP K is modified by SUMO in lysine 422 within its KH3 domain, and sumoylation is regulated by the E3 ligase Pc2/CBX4. Most interestingly, DNA damage stimulates hnRNP K sumoylation through Pc2 E3 activity, and this modification is required for p53 transcriptional activation. Abrogation of hnRNP K sumoylation leads to an aberrant regulation of the p53 target gene p21. Our findings link the DNA damage-induced Pc2 activation to the p53 transcriptional co-activation through hnRNP K sumoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA Damage*
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Humans
  • Ligases
  • Polycomb-Group Proteins / biosynthesis
  • Polycomb-Group Proteins / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Sumoylation*
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Polycomb-Group Proteins
  • Ribonucleoproteins
  • SUMO-1 Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • HNRNPK protein, human
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases
  • Ligases
  • CBX4 protein, human