title: Phosphorylation of the BRCA1 C terminus (BRCT) repeat inhibitor of hTERT (BRIT1) protein coordinates TopBP1 protein recruitment and amplifies ataxia telangiectasia-mutated and Rad3-related (ATR) Signaling.
abstract: The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase functions as a central node in the DNA damage response signaling network. The mechanisms by which ATR activity is amplified and/or maintained are not understood. Here we demonstrate that BRIT1/microcephalin (MCPH1), a human disease-related protein, is dispensable for the initiation but essential for the amplification of ATR signaling. BRIT1 interacts with and recruits topoisomerase-binding protein 1 (TopBP1), a key activator of ATR signaling, to the sites of DNA damage. Notably, replication stress-induced ataxia telangiectasia-mutated or ATR-dependent BRIT1 phosphorylation at Ser-322 facilitates efficient TopBP1 recruitment. These results reveal a mechanism that ensures the continuation of ATR-initiated DNA damage signaling. Our study uncovers a previously unknown regulatory axis of ATR signaling in maintaining genomic integrity, which may provide mechanistic insights into the perturbation of ATR signaling in human diseases such as neurodevelopmental defects and cancer.
authors.affiliation: From the Department of General Surgery, Union Hospital, Tongji Medical College, The University of Huazhong Science and Technology, Wuhan, Hubei Province 430022, China, Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: the Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054.
authors.forename: Edward
authors.initials: E
authors.lastname: Wang
authors.affiliation: the Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054.
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.affiliation: Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Hsieh
authors.affiliation: the Departments of Cancer Biology and.
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 gpeng@mdanderson.org.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C110513:TOPBP1 protein, human; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; BRIT1; Cancer Biology; Cell Cycle; Cell Signaling; DNA Damage; DNA Repair; MCPH1; Replication Stress; TopBP1