title: Nuclear GIT2 is an ATM substrate and promotes DNA repair.
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.
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Daoyuan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Metabolism Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Cai
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Park
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Sana
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Duke Brain Sciences Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.affiliation: Duke Brain Sciences Institute, Duke University, Durham, North Carolina, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schmalzigaug
authors.affiliation: Gene Targeting Section, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Paramasivam
authors.affiliation: Gene Targeting Section, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Seidman
authors.affiliation: Immunotherapeutics Section, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Ionoa
authors.initials: I
authors.lastname: Bodogai
authors.affiliation: Immunotherapeutics Section, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
authors.affiliation: Metabolism Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Daimon
authors.affiliation: Metabolism Unit, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, Baltimore, Maryland, USA VIB Department of Molecular Genetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium stuart.maudsley@molgen.vib-ua.be.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D020690:GTPase-Activating Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C430213:GIT2 protein, human; D020690:GTPase-Activating Proteins; C120767:Git2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D064007:Ataxia Telangiectasia Mutated Proteins