title: HERC2-USP20 axis regulates DNA damage checkpoint through Claspin.
abstract: The DNA damage response triggers cell-cycle checkpoints, DNA repair and apoptosis using multiple post-translational modifications as molecular switches. However, how ubiquitination regulates ATR signaling in response to replication stress and single-strand break is still unclear. Here, we identified the deubiquitination enzyme (DUB) USP20 as a pivotal regulator of ATR-related DDR pathway. Through screening a panel of DUBs, we identified USP20 as critical for replication stress response. USP20 is phosphorylated by ATR, resulting in disassociation of the E3 ubiquitin ligase HERC2 from USP20 and USP20 stabilization. USP20 in turn deubiquitinates and stabilizes Claspin and enhances the activation of ATR-Chk1 signaling. These findings reveal USP20 to be a novel regulator of ATR-dependent DNA damage signaling.
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China lou.zhenkun@mayo.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Puqiang
authors.initials: P
authors.lastname: Wu
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA lou.zhenkun@mayo.edu.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D010450:Endopeptidases / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C488158:CLSPN protein, human; D020662:Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; C459591:USP20 protein, human; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C486762:Usp20 protein, mouse