PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading

Elife. 2018 Jul 9;7:e38771. doi: 10.7554/eLife.38771.

Abstract

The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

Keywords: BMI1; DNA damage response; DNA repair; FBXL10; H2A.Z; MEL18; PARP; RNF2; RNF68; TIMELESS; chromosomes; gene expression; human.

Publication types

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

MeSH terms

  • Cell Line
  • DNA Damage*
  • DNA Repair / genetics
  • F-Box Proteins / chemistry
  • F-Box Proteins / metabolism*
  • Histones / metabolism*
  • Homologous Recombination / genetics
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Kinetics
  • Lysine / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Polycomb Repressive Complex 1 / metabolism*
  • Protein Domains
  • Protein Multimerization
  • Protein Subunits / metabolism
  • RNA, Small Interfering / metabolism
  • Transcription, Genetic
  • Ubiquitination

Substances

  • F-Box Proteins
  • Histones
  • Protein Subunits
  • RNA, Small Interfering
  • histone H2A.F-Z
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • Polycomb Repressive Complex 1
  • RNF2 protein, human
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Lysine