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  • Review Article
  • Published:

RecQ helicases: multifunctional genome caretakers

Nature Reviews Cancer volume 9, pages 644–654 (2009)Cite this article

Key Points

  • RecQ helicases are a highly conserved family and are considered to be genome 'caretakers' that maintain chromosome stability and suppress neoplastic transformation.

  • The crystal structure of RecQ helicases reveals several conserved functional domains. Some of these domains define a particular member of the RecQ helicase family and may be important for functionally distinguishing between the different RecQ helicases expressed in a particular organism.

  • Defects in three of the five human RecQ helicase members give rise to at least five defined disorders associated with cancer predisposition, premature ageing and developmental abnormalities. Mutations in BLM and WRN lead to Bloom's and Werner's syndromes, respectively, and RECQ4 is associated with three distinct disorders: Rothmund–Thomson, RAPADILINO and Baller–Gerold syndromes. These RECQ4 disorders display the common feature of an abnormality in bone development.

  • Mouse models of human RecQ helicase disorders have been generated that partially recapitulate the phenotypes seen in human patients.

  • RecQ helicases possess several biochemical activities and have several important roles in DNA replication and recombination. Some of these activities require or are modulated by physical interactions with other nuclear proteins.

  • BLM is proposed to have roles in mitosis that resolve late-replication intermediates in conjunction with topoisomerase IIIα. Together, these proteins probably function to decatenate entangled DNA that arises during DNA replication.

Abstract

Around 1% of the open reading frames in the human genome encode predicted DNA and RNA helicases. One highly conserved group of DNA helicases is the RecQ family. Genetic defects in three of the five human RecQ helicases, BLM, WRN and RECQ4, give rise to defined syndromes associated with cancer predisposition, some features of premature ageing and chromosomal instability. In recent years, there has been a tremendous advance in our understanding of the cellular functions of individual RecQ helicases. In this Review, we discuss how these proteins might suppress genomic rearrangements, and therefore function as 'caretaker' tumour suppressors.

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Figure 1: The RecQ family.
Figure 2: Structure of the Escherichia coli RecQ protein.
Figure 3: Examples of substrates unwound by one or more RecQ helicases.
Figure 4: Potential roles of RecQ helicases in preventing crossing over during homologous recombination (HR).
Figure 5: Mechanism of double Holliday junction dissolution catalysed by the BLM–Topoisomerase IIIα (TOPOIIIα)–RMI1–RMI2 complex.
Figure 6: Model for the disruption of late-replication intermediates (LRIs) by a RecQ helicase and topoisomerase IIIα (TOPOIIIα).

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Acknowledgements

We thank J. Keck for the RecQ protein structure, members of the Hickson laboratory for helpful discussions, and H. Mankouri, C. Bachrati and P. McHugh for helpful comments on the manuscript. Work in the authors' laboratory is funded by Cancer Research UK and the Bloom's Syndrome Foundation. W.K.C was supported by the Anita Mui 'True Heart' Charity Foundation, the K. P. Tin Foundation Limited and the China Oxford Scholarship Fund.

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  1. Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK

    Wai Kit Chu & Ian D. Hickson

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Correspondence to Ian D. Hickson.

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DATABASES

OMIM

Baller–Gerold syndrome

Bloom's syndrome

RAPADILINO syndrome

Rothmund–Thomson syndrome

Werner's syndrome

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Glossary

Globular fold

'Globe-like' region of a protein that is normally soluble in aqueous solution.

Promyelocytic leukaemia nuclear bodies

Focal nuclear structures that are defined by the presence of PML, which forms an oncogenic fusion protein in cases of acute promyelocytic leukaemia.

Nonsense-mediated mRNA decay

A quality-control mechanism that selectively degrades mRNAs harbouring premature termination codons.

Hypomorphic

An allele that results in a reduction, but not the elimination, of wild-type levels of gene product or activity. This often causes a less severe phenotype than a loss-of-function (or null) allele.

Osteoporosis

Reduction of bone mineral density.

Craniosynostosis

Abnormal skull and brain growth owing to premature fusion of the cranial sutures.

Poikiloderma

Reticulated (lattice-like) cutaneous plaques.

Branch migration

Movement of a DNA crossover junction, causing symmetrical exchange of DNA strands and symmetrical formation of a DNA heteroduplex.

OB-fold

Oligonucleotide and oligosaccharide-binding fold domain of a protein.

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Chu, W., Hickson, I. RecQ helicases: multifunctional genome caretakers. Nat Rev Cancer 9, 644–654 (2009). https://doi.org/10.1038/nrc2682

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