title: Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks.
abstract: Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single-stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability.
authors.affiliation: Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, 4102, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Bolderson
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Petermann
authors.affiliation: Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, 4102, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Croft
authors.affiliation: Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, 4102, Australia.
authors.forename: Amila
authors.initials: A
authors.lastname: Suraweera
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia kumkumk@qimrberghofer.edu.au.
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.affiliation: Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, 4102, Australia derek.richard@qut.edu.au.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Richard
mesh_terms: D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002470:Cell Survival; D002843:Chromatin / Q000737:chemistry; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C504091:NABP2 protein, human
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