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: Martin Borch Jensen, Christopher A Dunn, Guido Keijzers, Tomasz Kulikowicz, Lene Juel Rasmussen, Deborah L Croteau, Vilhelm A Bohr
• Journal: Aging (Aging (Albany NY)) Vol. 4 Issue 11 Pg. 790-802 (Nov 2012) ISSN: 1945-4589 [Electronic] United States
• PMID: 23238538 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Adenosine Triphosphatases
• RECQL4 protein, human
• RecQ Helicases

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Amino Acid Sequence
• Humans
• Molecular Sequence Data
• Mutation
• Protein Structure, Quaternary
• RecQ Helicases (genetics, metabolism)
• Structural Homology, Protein