title: Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair.
abstract: Inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (IP(7)), are water-soluble inositol phosphates that contain high energy diphosphate moieties on the inositol ring. Inositol hexakisphosphate kinase 1 (IP6K1) participates in inositol pyrophosphate synthesis, converting inositol hexakisphosphate (IP(6)) to IP(7). In the present study, we show that mouse embryonic fibroblasts (MEFs) lacking IP6K1 exhibit impaired DNA damage repair via homologous recombination (HR). IP6K1 knock-out MEFs show decreased viability and reduced recovery after induction of DNA damage by the replication stress inducer, hydroxyurea, or the radiomimetic antibiotic, neocarzinostatin. Cells lacking IP6K1 arrest after genotoxic stress, and markers associated with DNA repair are recruited to DNA damage sites, indicating that HR repair is initiated in these cells. However, repair does not proceed to completion because these markers persist as nuclear foci long after drug removal. A fraction of IP6K1-deficient MEFs continues to proliferate despite the persistence of DNA damage, rendering the cells more susceptible to chromosomal aberrations. Expression of catalytically active but not inactive IP6K1 can restore the repair process in knock-out MEFs, implying that inositol pyrophosphates are required for HR-mediated repair. Our study therefore highlights inositol pyrophosphates as novel small molecule regulators of HR signaling in mammals.
authors.affiliation: Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500001, India.
authors.forename: Rathan S
authors.initials: RS
authors.lastname: Jadav
authors.forename: Manasa V L
authors.initials: MV
authors.lastname: Chanduri
authors.forename: Sagar
authors.initials: S
authors.lastname: Sengupta
authors.forename: Rashna
authors.initials: R
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle; D002470:Cell Survival; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D007295:Inositol Phosphates / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D059767:Recombinational DNA Repair
chemical_list: D015415:Biomarkers; C485444:Ihpk1 protein, mouse; D007295:Inositol Phosphates; C079849:1-diphosphoinositol pentakisphosphate; D017856:Phosphotransferases (Phosphate Group Acceptor)