title: The helicase and ATPase activities of RECQL4 are compromised by mutations reported in three human patients.
abstract: RECQL4 is one of five members of the human RecQ helicase family, and is implicated in three syndromes displaying accelerating aging, developmental abnormalities and a predisposition to cancer. In this study, we purified three variants of RECQL4 carrying previously reported patient mutations. These three mutant proteins were analyzed for the known biochemical activities of RECQL4: DNA binding, unwinding of duplex DNA, ATP hydrolysis and annealing of simplex DNA. Further, the mutant proteins were evaluated for stability and recruitment to sites of laser-induced DNA damage. One mutant was helicase-dead, had marginal ATPase activity and may be structurally compromised, while the other two showed greatly reduced helicase and ATPase activities. The remaining biochemical activities and ability to recruit to damage sites were not significantly impaired for any of the mutants. Our findings demonstrate a consistent pattern of functional deficiency and provide further support for a helicase-dependent cellular function of RECQL4 in addition to its N-terminus-dependent role in initiation of replication, a function that may underlie the phenotype of RECQL4-linked disease.
authors.affiliation: Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Martin Borch
authors.initials: MB
authors.lastname: Jensen
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Dunn
authors.forename: Guido
authors.initials: G
authors.lastname: Keijzers
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kulikowicz
authors.forename: Lene Juel
authors.initials: LJ
authors.lastname: Rasmussen
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D000251:Adenosine Triphosphatases; C506731:RECQL4 protein, human; D053484:RecQ Helicases