title: The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability.
abstract: Bacteria and yeast possess one RecQ helicase homolog whereas humans contain five RecQ helicases, all of which are important in preserving genome stability. Three of these, BLM, WRN and RECQL4, are mutated in human diseases manifesting in premature aging and cancer. We are interested in determining to which extent these RecQ helicases function cooperatively. Here, we report a novel physical and functional interaction between BLM and RECQL4. Both BLM and RECQL4 interact in vivo and in vitro. We have mapped the BLM interacting site to the N-terminus of RECQL4, comprising amino acids 361-478, and the region of BLM encompassing amino acids 1-902 interacts with RECQL4. RECQL4 specifically stimulates BLM helicase activity on DNA fork substrates in vitro. The in vivo interaction between RECQL4 and BLM is enhanced during the S-phase of the cell cycle, and after treatment with ionizing radiation. The retention of RECQL4 at DNA double-strand breaks is shortened in BLM-deficient cells. Further, depletion of RECQL4 in BLM-deficient cells leads to reduced proliferative capacity and an increased frequency of sister chromatid exchanges. Together, our results suggest that BLM and RECQL4 have coordinated activities that promote genome stability.
authors.affiliation: Laboratory of Molecular Gerontology, Biomedical Research Center, 251 Bayview Boulevard, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Dharmendra Kumar
authors.initials: DK
authors.lastname: Singh
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Popuri
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kulikowicz
authors.forename: Igor
authors.initials: I
authors.lastname: Shevelev
authors.forename: Avik K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramamoorthy
authors.forename: Marie L
authors.initials: ML
authors.lastname: Rossi
authors.forename: Pavel
authors.initials: P
authors.lastname: Janscak
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D042822:Genomic Instability; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054730:Protein Interaction Domains and Motifs; D053484:RecQ Helicases / Q000737:chemistry / Q000378:metabolism*; D016196:S Phase; D012854:Sister Chromatid Exchange; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C029389:thymine glycol; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; C097151:Bloom syndrome protein; C506731:RECQL4 protein, human; D053484:RecQ Helicases; D013941:Thymine