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Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance

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The RecQ helicases are guardians of the genome. Members of this conserved family of proteins have a key role in protecting and stabilizing the genome against deleterious changes. Deficiencies in RecQ helicases can lead to high levels of genomic instability and, in humans, to premature aging and increased susceptibility to cancer. Their diverse roles in DNA metabolism, which include a role in telomere maintenance, reflect interactions with multiple cellular proteins, some of which are multifunctional and also have very diverse functions. The results of in vitro cellular and biochemical studies have been complimented by recent in vivo studies using genetically modified mouse strains. Together, these approaches are helping to unravel the mechanism(s) of action and biological functions of the RecQ helicases.

Section snippets

RecQ helicases: guardians of the genome

The RecQ protein family is a highly conserved group of DNA helicases with diverse roles in multiple DNA metabolic processes, including DNA recombination, replication and repair, and a possible role in transcription. Only one RecQ homolog has been identified in Escherichia coli and the lower eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe, but five RecQ homologs have been identified in mammals, including humans. The human RecQ helicases include WRN (Werner), BLM (Bloom), RECQ4,

The RecQ family

E. coli RecQ is the prototypical member of the RecQ helicase family. Alignment of E. coli RecQ with other RecQ family members reveals strong conservation of the helicase domain (Figure 1). This amino acid sequence conservation is reflected in the functional DNA helicase activity found in all RecQ homologs with the exception of RECQ4 [3]. The RQC (RecQ conserved) domain is less well conserved than the helicase domain but is present in most RecQ family members, including E.coli RecQ. However, the

RecQ helicase syndromes

Several of the clinical features of WS and BS are identical, whereas other clinical features are unique to one or the other syndrome (Figure 4). Clinical features common to WS and BS include slow growth, abnormal facial features, infertility and high incidence and/or early onset of aging-related diseases. WS patients have a more pronounced premature-aging phenotype and, unlike normal individuals and BS patients, WS patients are highly susceptible to early onset of mesenchymal tumors such as

RecQ helicases and DNA repair

Cellular DNA is continuously damaged by exogenous and endogenous agents and chemicals, which together generate many types of lesions throughout the genome. Many of the oxidative DNA modifications that accumulate in nucleic acids over time are thought to be caused by endogenous reactive oxygen species (ROS), which are produced as normal by-products of oxidative phosphorylation in mitochondria and other metabolic processes. It has been estimated that 50 000–100 000 oxidative DNA lesions are

RecQ helicases and telomere maintenance

Early studies of WS fibroblasts revealed that WRN deficiency is associated with a defect in telomere maintenance [84]. Furthermore, in vitro experiments with oligomeric telomere substrates demonstrated that WRN processes telomeric DNA and activates a DNA damage response [85]. Previous studies showed that WRN and BLM both interact with telomere proteins TRF1 and TRF2 86, 87, both of which are components of shelterin, a protein complex involved in telomere maintenance. WRN is enriched at the

Post-translational modification of RecQ helicases

Early studies identified post-translational modifications of RecQ helicases, some of which might have a regulatory role (Figure 7). For example, WRN is phosphorylated on serine, threonine and tyrosine residues in vitro and in vivo. Phosphorylation of WRN increases in cells exposed to bleomycin or other types of replication stress 64, 93. Bleomycin-induced serine/threonine phosphorylation of WRN requires ataxia telangiectasia mutated protein (ATM) and the DNA-PK complex, as it is not observed in

Conclusions

RecQ helicases have an important role in maintaining genome stability. Defects in RecQ helicases are associated with susceptibility to cancer and premature aging in humans and genome instability and hypersensitivity to DNA damaging agents in cultured cells. Purified RecQ helicases from higher organisms bind preferentially to DNA substrates that resemble intermediates in DNA repair, replication or recombination. Extensive characterization of the human RecQ helicases indicates that they have

Acknowledgements

I would like to thank M. Sander, D. Wilson and D. Croteau for suggestions. I acknowledge support from the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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