Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

Abstract

Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.Key words: aging, cancer, DNA repair, genomic instability, helicase, RecQ. INTRODUCTIONUnderstanding the molecular mechanisms of RecQ helicases is fundamental to deciphering the roles of these enzymes in cellular DNA metabolism. Since the discovery of Escherichia coli RecQ and its implicated role in genetic recombination, the world of RecQ helicases has become significantly more complex with the identification and characterization of a number of eukaryotic RecQ helicases that are important in the replicational stress response and maintenance of genomic stability.Classification of RecQ helicases and molecular-genetic analyses of their biochemical and cellular functions gained prominence with the understanding that certain rare genetic disorders [WS (Werner syndrome), BS (Bloom syndrome) and RTS (Rothmund-Thomson syndrome)] are a consequence of mutations in the human RecQ genes WRN, BLM and RECQ4 respectively. WS is characterized by premature aging with an elevated risk of age-associated diseases such as cancer, atherosclerotic cardiovascular disease, diabetes mellitus (Type II) and osteoporosis [1]. Epigenetic inactivation of WRN is detected in a number of human cancers [2]. BS is associated with a very high incidence of different types of cancers, both solid tumours and leukaemia, and also manifested by skin disorders, proportional dwarfism, immunodeficiency and male sterility [1]. People with RTS, also known as poikiloderma congenitale, displays growth deficiency, photosensitivity with poikilodermatous skin changes, early greying and hair loss, juvenile cataracts and a predisposition to malignancy, especially osteogenic sarcomas [1]. Apart from RTS, RECQ4 mutations were detected in Finnish patients with an autosomal recessive disorder RAPADILINO syndrome [radial hypoplasia/aplasia, patellae hypoplasia/aplasia and cleft or highly arched palate, diarrhoea and dislocated joints, little size (height at least 2 S.D. smaller than the average height) and limb malformation, nose slender and normal intelligence] [3]. Although many features o...

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“…Other characterized mammalian helicases do not exhibit extensive redundancy in vivo. For example, the five known RecQ helicases (Wrn, Blm, RecQ4, RecQL, and RecQ5b) and XPB/ ERCC3 (implicated in xeroderma pigmentosum and Cockayne syndrome) show limited redundancy in rescuing p53-dependent apoptosis in Bloom-deficient cells (63); however, mutations in each helicase gene have distinct phenotypes in genome stability and DNA replication and repair in vivo and all are separately implicated in human disease (8,34,49,62).…”

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“…BLM is an ATP-dependent 3 0 -5 0 DNA helicase involved in unwinding a variety of DNA substrates that can arise during DNA replication and repair (1)(2)(3)(4)(5). BLM has important roles in the initiation and regulation of homologous recombination (HR) repair of double-strand breaks (DSB).…”

“…BLM is also part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, PMS2, and the RAD50-MRE11-NBS1 protein complex (6). In addition to its DNA repair function, BLM is involved in the processing of stalled replication forks during replication and in telomere maintenance in cells (1)(2)(3)(4)(5).…”

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“…Multimerization potentially affects substrate specificities and enzymatic activities of the full-length WRN protein. The multimerization state of WRN homologues is still under debate (Sharma et al, 2006), but the human homolog BLM has been observed to form hexameric and/or tetrameric rings (Karow et al, 1999). A WRN exonuclease hexameric ring model (Fig.…”

“…6a) and structural studies on the protein's domains and those of homologues are helping to define WRN mediated functions (Killoran and Keck, 2006). The N-terminus of WRN contains the exonuclease domain, the central core contains the helicase region and in the C-terminus two regions have been identified that bind protein partners and/or DNA (Sharma et al, 2006). Crystallographic and structure based mutational studies on the WRN exonuclease domain, have revealed a high degree of structural and mechanistic conservation with the DnaQ family of replicative proofreading exonucleases (Fig.…”