title: PHF11 promotes DSB resection, ATR signaling, and HR.
abstract: Resection of double-strand breaks (DSBs) plays a critical role in their detection and appropriate repair. The 3' ssDNA protrusion formed through resection activates the ATR-dependent DNA damage response (DDR) and is required for DSB repair by homologous recombination (HR). Here we report that PHF11 (plant homeodomain finger 11) encodes a previously unknown DDR factor involved in 5' end resection, ATR signaling, and HR. PHF11 was identified based on its association with deprotected telomeres and localized to sites of DNA damage in S phase. Depletion of PHF11 diminished the ATR signaling response to telomere dysfunction and genome-wide DNA damage, reduced end resection at sites of DNA damage, resulted in compromised HR and misrejoining of S-phase DSBs, and increased the sensitivity to DNA-damaging agents. PHF11 interacted with the ssDNA-binding protein RPA and was found in a complex with several nucleases, including the 5' dsDNA exonuclease EXO1. Biochemical experiments demonstrated that PHF11 stimulates EXO1 by overcoming its inhibition by RPA, suggesting that PHF11 acts (in part) by promoting 5' end resection at RPA-bound sites of DNA damage. These findings reveal a role for PHF11 in DSB resection, DNA damage signaling, and DSB repair.
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California at Davis, Davis, California 95616, USA.|Department of Molecular and Cellular Biology, University of California at Davis, Davis, California 95616, USA.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Handa
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California at Davis, Davis, California 95616, USA.|Department of Molecular and Cellular Biology, University of California at Davis, Davis, California 95616, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Kowalczykowski
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D000818:Animals; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005090:Exodeoxyribonucleases / Q000378:metabolism; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D051379:Mice; D021381:Protein Transport; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000599490:PHF11 protein, mouse; D014157:Transcription Factors; D005090:Exodeoxyribonucleases; C028450:exodeoxyribonuclease I
keywords: ATR; DSB; EXO1; PHF11; RPA; homologous recombination; resection