title: The RECQL4 protein, deficient in Rothmund-Thomson syndrome is active on telomeric D-loops containing DNA metabolism blocking lesions.
abstract: Telomeres are critical for cell survival and functional integrity. Oxidative DNA damage induces telomeric instability and cellular senescence that are associated with normal aging and segmental premature aging disorders such as Werner Syndrome and Rothmund-Thomson Syndrome, caused by mutations in WRN and RECQL4 helicases respectively. Characterizing the metabolic roles of RECQL4 and WRN in telomere maintenance is crucial in understanding the pathogenesis of their associated disorders. We have previously shown that WRN and RECQL4 display a preference in vitro to unwind telomeric DNA substrates containing the oxidative lesion 8-oxoguanine. Here, we show that RECQL4 helicase has a preferential activity in vitro on telomeric substrates containing thymine glycol, a critical lesion that blocks DNA metabolism, and can be modestly stimulated further on a D-loop structure by TRF2, a telomeric shelterin protein. Unlike that reported for telomeric D-loops containing 8-oxoguanine, RECQL4 does not cooperate with WRN to unwind telomeric D-loops with thymine glycol, suggesting RECQL4 helicase is selective for the type of oxidative lesion. RECQL4's function at the telomere is not yet understood, and our findings suggest a novel role for RECQL4 in the repair of thymine glycol lesions to promote efficient telomeric maintenance.
authors.affiliation: The Laboratory of Molecular Gerontology, National Institute on Aging, 251 Bayview Boulevard, Baltimore, MD 21224, USA. lesliekhoh@yahoo.com
authors.forename: Leslie K
authors.initials: LK
authors.lastname: Ferrarelli
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Popuri
authors.forename: Avik K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Takashi
authors.initials: T
authors.lastname: Tadokoro
authors.forename: Chandrika
authors.initials: C
authors.lastname: Canugovi
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Hsu
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005090:Exodeoxyribonucleases / Q000378:metabolism; D006801:Humans; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000378:metabolism*; D011038:Rothmund-Thomson Syndrome / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism; D000071657:Werner Syndrome Helicase
chemical_list: D018736:DNA Adducts; D017382:Reactive Oxygen Species; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C029389:thymine glycol; D004247:DNA; D005090:Exodeoxyribonucleases; C506731:RECQL4 protein, human; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D013941:Thymine