Nuclear GIT2 is an ATM substrate and promotes DNA repair

Mol Cell Biol. 2015 Apr;35(7):1081-96. doi: 10.1128/MCB.01432-14. Epub 2015 Jan 20.

Abstract

Insults to nuclear DNA induce multiple response pathways to mitigate the deleterious effects of damage and mediate effective DNA repair. G-protein-coupled receptor kinase-interacting protein 2 (GIT2) regulates receptor internalization, focal adhesion dynamics, cell migration, and responses to oxidative stress. Here we demonstrate that GIT2 coordinates the levels of proteins in the DNA damage response (DDR). Cellular sensitivity to irradiation-induced DNA damage was highly associated with GIT2 expression levels. GIT2 is phosphorylated by ATM kinase and forms complexes with multiple DDR-associated factors in response to DNA damage. The targeting of GIT2 to DNA double-strand breaks was rapid and, in part, dependent upon the presence of H2AX, ATM, and MRE11 but was independent of MDC1 and RNF8. GIT2 likely promotes DNA repair through multiple mechanisms, including stabilization of BRCA1 in repair complexes; upregulation of repair proteins, including HMGN1 and RFC1; and regulation of poly(ADP-ribose) polymerase activity. Furthermore, GIT2-knockout mice demonstrated a greater susceptibility to DNA damage than their wild-type littermates. These results suggest that GIT2 plays an important role in MRE11/ATM/H2AX-mediated DNA damage responses.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Cycle Proteins / analysis
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • DNA Damage*
  • DNA Repair*
  • GTPase-Activating Proteins / analysis
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Phosphoproteins / analysis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*

Substances

  • Cell Cycle Proteins
  • GIT2 protein, human
  • GTPase-Activating Proteins
  • Git2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Ataxia Telangiectasia Mutated Proteins