title: DNA damage-induced BARD1 phosphorylation is critical for the inhibition of messenger RNA processing by BRCA1/BARD1 complex.
abstract: BRCA1-associated RING domain protein BARD1, along with its heterodimeric partner BRCA1, plays important roles in cellular response to DNA damage. Immediate cellular response to genotoxic stress is mediated by a family of phosphoinositide 3-kinase-related protein kinases, such as ataxia-telangiectasia mutated (ATM), ATM and Rad3-related, and DNA-dependent protein kinase. ATM-mediated phosphorylation of BRCA1 enhances the DNA damage checkpoint functions of BRCA1, but how BARD1 is regulated during DNA damage signaling has not been examined. Here, we report that BARD1 undergoes phosphorylation upon ionizing radiation or UV radiation and identify Thr(714) as the in vivo BARD1 phosphorylation site. Importantly, DNA damage functions of BARD1 (i.e., inhibition of pre-mRNA polyadenylation and degradation of RNA polymerase II) are abrogated in T714A and T734A mutants. Our findings suggest that phosphorylation of BARD1 is critical for the DNA damage functions of the BRCA1/BARD1 complex.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Ho-Shik
authors.initials: HS
authors.lastname: Kim
authors.forename: Hongjie
authors.initials: H
authors.lastname: Li
authors.forename: Murat
authors.initials: M
authors.lastname: Cevher
authors.forename: Alissa
authors.initials: A
authors.lastname: Parmelee
authors.forename: Danae
authors.initials: D
authors.lastname: Fonseca
authors.forename: Frida Esther
authors.initials: FE
authors.lastname: Kleiman
authors.forename: Sean Bong
authors.initials: SB
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects
chemical_list: D019313:BRCA1 Protein; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases