Mechanistic insight into the interaction of BLM helicase with intra-strand G-quadruplex structures

Sujoy Chatterjee, Jennifer Zagelbaum, Pavel Savitsky, Andreas Sturzenegger, Diana Huttner, Pavel Janscak, Ian D. Hickson, Opher Gileadi and Eli Rothenberg ()
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Sujoy Chatterjee: New York University School of Medicine
Jennifer Zagelbaum: New York University School of Medicine
Pavel Savitsky: Genome Integrity group, Structural Genomics Consortium, University of Oxford
Andreas Sturzenegger: Institute of Molecular Cancer Research, University of Zurich
Diana Huttner: NovoNordisk Foundation Center for Protein Research, University of Copenhagen
Pavel Janscak: Institute of Molecular Cancer Research, University of Zurich
Ian D. Hickson: University of Copenhagen
Opher Gileadi: Genome Integrity group, Structural Genomics Consortium, University of Oxford
Eli Rothenberg: New York University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Bloom syndrome is an autosomal recessive disorder caused by mutations in the RecQ family helicase BLM that is associated with growth retardation and predisposition to cancer. BLM helicase has a high specificity for non-canonical G-quadruplex (G4) DNA structures, which are formed by G-rich DNA strands and play an important role in the maintenance of genomic integrity. Here we used single-molecule FRET to define the mechanism of interaction of BLM helicase with intra-stranded G4 structures. We show that the activity of BLM is substrate dependent, and highly regulated by a short-strand DNA (ssDNA) segment that separates the G4 motif from double-stranded DNA. We demonstrate cooperativity between the RQC and HRDC domains of BLM during binding and unfolding of the G4 structure, where the RQC domain interaction with G4 is stabilized by HRDC binding to ssDNA. We present a model that proposes a unique role for G4 structures in modulating the activity of DNA processing enzymes.

Date: 2014
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DOI: 10.1038/ncomms6556

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