title: Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs.
abstract: Mammalian HELQ is a 3'-5' DNA helicase with strand displacement activity. Here we show that HELQ participates in a pathway of resistance to DNA interstrand crosslinks (ICLs). Genetic disruption of HELQ in human cells enhances cellular sensitivity and chromosome radial formation by the ICL-inducing agent mitomycin C (MMC). A significant fraction of MMC sensitivity is independent of the Fanconi anaemia pathway. Sister chromatid exchange frequency and sensitivity to UV radiation or topoisomerase inhibitors is unaltered. Proteomic analysis reveals that HELQ is associated with the RAD51 paralogs RAD51B/C/D and XRCC2, and with the DNA damage-responsive kinase ATR. After treatment with MMC, reduced phosphorylation of the ATR substrate CHK1 occurs in HELQ-knockout cells, and accumulation of G2/M cells is reduced. The results indicate that HELQ operates in an arm of DNA repair and signalling in response to ICL. Further, the association with RAD51 paralogs suggests HELQ as a candidate ovarian cancer gene.
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center Science Park, Smithville, TX 78957, USA.
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Takata
authors.forename: Shelley
authors.initials: S
authors.lastname: Reh
authors.forename: Junya
authors.initials: J
authors.lastname: Tomida
authors.forename: Maria D
authors.initials: MD
authors.lastname: Person
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012854:Sister Chromatid Exchange / Q000187:drug effects
chemical_list: D003432:Cross-Linking Reagents; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D050505:Mutant Proteins; D016685:Mitomycin; D004247:DNA; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D004265:DNA Helicases; C451406:HELQ protein, human