title: A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.
abstract: BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator.
authors.affiliation: School of Life Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Panfei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Correia
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Seungbaek
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Jungjin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Physiology, Washington University, St Louis, Missouri 63130, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Sparks
authors.affiliation: BSI-Genetics &Bioinformatics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Evans
authors.affiliation: BSI-Genetics &Bioinformatics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Molecular Pharmacology and Experimental therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Physiology, Washington University, St Louis, Missouri 63130, USA.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: You
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.|Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.|Molecular Pharmacology and Experimental therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D044767:Ubiquitin-Protein Ligases
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases