title: ATM-dependent Phosphorylation of the Fanconi Anemia Protein PALB2 Promotes the DNA Damage Response.
abstract: The Fanconi anemia protein PALB2, also known as FANCN, protects genome integrity by regulating DNA repair and cell cycle checkpoints. Exactly how PALB2 functions may be temporally coupled with detection and signaling of DNA damage is not known. Intriguingly, we found that PALB2 is transformed into a hyperphosphorylated state in response to ionizing radiation (IR). IR treatment specifically triggered PALB2 phosphorylation at Ser-157 and Ser-376 in manners that required the master DNA damage response kinase Ataxia telangiectasia mutated, revealing potential mechanistic links between PALB2 and the Ataxia telangiectasia mutated-dependent DNA damage responses. Consistently, dysregulated PALB2 phosphorylation resulted in sustained activation of DDRs. Full-blown PALB2 phosphorylation also required the breast and ovarian susceptible gene product BRCA1, highlighting important roles of the BRCA1-PALB2 interaction in orchestrating cellular responses to genotoxic stress. In summary, our phosphorylation analysis of tumor suppressor protein PALB2 uncovers new layers of regulatory mechanisms in the maintenance of genome stability and tumor suppression.
authors.affiliation: From the School of Biomedical Sciences.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the School of Biomedical Sciences.
authors.forename: Wanjuan
authors.initials: W
authors.lastname: Feng
authors.affiliation: From the School of Biomedical Sciences, Centre for Cancer Research, LKS Faculty of Medicine, mhsy@hku.hk.
authors.forename: Shirley M H
authors.initials: SM
authors.lastname: Sy
authors.affiliation: From the School of Biomedical Sciences, Centre for Cancer Research, LKS Faculty of Medicine, State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong huen.michael@hku.hk.
authors.forename: Michael S Y
authors.initials: MS
authors.lastname: Huen
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011839:Radiation, Ionizing; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: BRCA1; DNA damage; DNA damage response; phosphorylation; protein phosphorylation