title: FBXL5-mediated degradation of single-stranded DNA-binding protein hSSB1 controls DNA damage response.
abstract: Human single-strand (ss) DNA binding proteins 1 (hSSB1) has been shown to participate in DNA damage response and maintenance of genome stability by regulating the initiation of ATM-dependent signaling. ATM phosphorylates hSSB1 and prevents hSSB1 from ubiquitin-proteasome-mediated degradation. However, the E3 ligase that targets hSSB1 for destruction is still unknown. Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. Furthermore, cells overexpression of Fbxl5 abrogated the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets and exhibited increased radiosensitivity, chemosensitivity and defective checkpoint activation after genotoxic stress stimuli. Moreover, the protein levels of hSSB1 and Fbxl5 showed an inverse correlation in lung cancer cells lines and clinical lung cancer samples. Therefore, Fbxl5 may negatively modulate hSSB1 to regulate DNA damage response, implicating Fbxl5 as a novel, promising therapeutic target for lung cancers.
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Chen
authors.affiliation: Key Laboratory of Kidney Disease Pathogenesis and Intervention of Hubei Province, College of Medicine, Hubei Polytechnic University, Huangshi, Hubei 435003, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Nai-Wang
authors.initials: NW
authors.lastname: Tang
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Yun-Hua
authors.initials: YH
authors.lastname: Xu
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Xiang-Yun
authors.initials: XY
authors.lastname: Ye
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Zi-Ming
authors.initials: ZM
authors.lastname: Li
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Niu
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Shen
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China shunlu_2014@126.com.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, People's Republic of China drxuling@126.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology; D054875:Ubiquitination
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C521741:FBXL5 protein, human; D024101:Mitochondrial Proteins; C504091:NABP2 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins