title: FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress.
abstract: Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)-binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.
authors: Department of Pathology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors: Yeon-Tae
authors: YT
authors: Jeong
authors: Mario
authors: M
authors: Rossi
authors: Lukas
authors: L
authors: Cermak
authors: Anita
authors: A
authors: Saraf
authors: Laurence
authors: L
authors: Florens
authors: Michael P
authors: MP
authors: Washburn
authors: Patrick
authors: P
authors: Sung
authors: Carl L
authors: CL
authors: Schildkraut
authors: Carl
authors: C
authors: Schildkraut
authors: Michele
authors: M
authors: Pagano
mesh_terms: D017209:Apoptosis; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051716:Replication Protein A / Q000378:metabolism / Q000502:physiology; D016196:S Phase; D013312:Stress, Physiological; D014466:Ultraviolet Rays
chemical_list: D004268:DNA-Binding Proteins; C497167:RPA1 protein, human; D051716:Replication Protein A; D004265:DNA Helicases; C464443:FBH1 protein, human; D006918:Hydroxyurea