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Nat Commun. 2014 Nov 24;5:5556. doi: 10.1038/ncomms6556.

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

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, MSB 394, 550 First Avenue, New York, New York 10016, USA.
2
Genome Integrity group, Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
3
Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland.
4
1] NovoNordisk Foundation Center for Protein Research, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
5
Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.

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.

PMID:
25418155
PMCID:
PMC4243535
DOI:
10.1038/ncomms6556
[Indexed for MEDLINE]
Free PMC Article

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