title: Tumor suppressor RecQL5 controls recombination induced by DNA crosslinking agents.
abstract: RecQ family DNA helicases function in the maintenance of genome stability. Mice deficient in RecQL5, one of five RecQ helicases, show a cancer predisposition phenotype, suggesting that RecQL5 plays a tumor suppressor role. RecQL5 interacts with Rad51, a key factor in homologous recombination (HR), and displaces Rad51 from Rad51-single stranded DNA (ssDNA) filaments in vitro. However, the precise roles of RecQL5 in the cell remain elusive. Here, we present evidence suggesting that RecQL5 is involved in DNA interstrand crosslink (ICL) repair. Chicken DT40 RECQL5 gene knockout (KO) cells showed sensitivity to ICL-inducing agents such as cisplatin (CDDP) and mitomycin C (MMC) and a higher number of chromosome aberrations in the presence of MMC than wild-type cells. The phenotypes of RECQL5 KO cells resembled those of Fanconi anemia gene KO cells. Genetic analysis using corresponding gene knockout cells showed that RecQL5 is involved in the FANCD1 (BRCA2)-dependent ICL repair pathway in which Rad51-ssDNA filament formation is promoted by BRCA2. The disappearance but not appearance of Rad51-foci was delayed in RECQL5 KO cells after MMC treatment. Deletion of Rad54, which processes the Rad51-ssDNA filament in HR, in RECQL5 KO cells increased sensitivity to CDDP and further delayed the disappearance of Rad51-foci, suggesting that RecQL5 and Rad54 have different effects on the Rad51-ssDNA filament. Furthermore, the frequency and variation of CDDP-induced gene conversion at the immunoglobulin locus were increased in RECQL5 KO cells. These results suggest that RecQL5 plays a role in regulating the incidence and quality of ICL-induced recombination.
authors.affiliation: Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hosono
authors.affiliation: IFOM, the FIRC Institute for Molecular Oncology Foundation, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Takuya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ishiai
authors.affiliation: Laboratory of Genetics, NIA, National Institutes of Health, NIH Biomedical Research Center, Baltimore, MD 21224, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: M Nurul
authors.initials: MN
authors.lastname: Islam
authors.affiliation: IFOM, the FIRC Institute for Molecular Oncology Foundation, IFOM-IEO Campus, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Laboratory of Genetics, NIA, National Institutes of Health, NIH Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Shujitsu University, School of Pharmacy, Nishigawara, Naka-ku, Okayama 703-8516, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Laboratory of DNA Damage Signaling, Department of Late Effect Studies, Radiation Biology Center, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.affiliation: Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan; Department of Biochemistry, Tohoku Pharmaceutical University, 4-1, Komatsushima 4-chome, Aoba-ku, Sendai, Miyagi 981-8558, Japan. Electronic address: t_eno@musashino-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Seki
authors.affiliation: Molecular Cell Biology Laboratory, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan. Electronic address: t_eno@musashino-u.ac.jp.
authors.forename: Takemi
authors.initials: T
authors.lastname: Enomoto
mesh_terms: D000818:Animals; D002460:Cell Line; D002645:Chickens; D004247:DNA / Q000737:chemistry*; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D053484:RecQ Helicases / Q000502:physiology*; D011995:Recombination, Genetic / Q000502:physiology*
chemical_list: C506732:RECQL5 protein, human; D004247:DNA; D053484:RecQ Helicases
keywords: BRCA2; Fanconi anemia; ICL repair; Rad51 filament; RecQL5; Tumor suppressor