Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology.

Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA.
Seminars in Cancer Biology (Impact Factor: 9.14). 10/2010; 20(5):329-39. DOI: 10.1016/j.semcancer.2010.10.002
Source: PubMed

ABSTRACT Helicases use the energy of ATP hydrolysis to separate double-stranded nucleic acids to facilitate essential processes such as replication, recombination, transcription and repair. This article focuses on the human RECQ helicase gene and protein family. Loss of function of three different members has been shown to cause Bloom syndrome (BS), Werner syndrome (WS) and Rothmund-Thomson syndrome (RTS). This article outlines clinical and cellular features of these cancer predisposition syndromes, and discusses their pathogenesis in light of our understanding of RECQ helicase biochemical activities and in vivo functions. I also discuss the emerging role for RECQ helicases as predictors of disease risk and the response to therapy.

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    ABSTRACT: Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny. These mutations affect varying genomic sizes ranging from single nucleotides to entire chromosomes and have been implicated in disease, most prominently cancer. The phenotypic consequences of somatic mosaicism are dependent upon many factors including the developmental time at which the mutation occurs, the areas of the body that are affected, and the pathophysiological effect(s) of the mutation. The advent of second-generation sequencing technologies has augmented existing array-based and cytogenetic approaches for the identification of somatic mutations. We outline the strengths and weaknesses of these techniques and highlight recent insights into the role of somatic mosaicism in causing cancer, neurodegenerative, monogenic, and complex disease.
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    ABSTRACT: RECQ1 is the most abundant member of the human RecQ family of DNA helicases genetically linked with cancer predisposition syndromes and well known for their functions in genome stability maintenance through DNA repair. Despite being the first discovered RecQ homolog in humans, biological functions of RECQ1 have remained largely underappreciated and its relevance to cellular transformation is yet unclear. RECQ1 is overexpressed and amplified in many clinical cancer samples. In silico evaluation of RECQ1 mRNA expression across the NCI-60 cancer cell lines predicts an association of RECQ1 with cancer cell migration, invasion, and metastasis. Consistent with this, latest work implicates RECQ1 in regulation of gene expression, especially of those associated with cancer progression. Functionally, silencing RECQ1 expression significantly reduces cell proliferation, migration, and invasion. Collectively, these results propose that discerning the role of RECQ1 in conferring proliferative and invasive phenotype to cancer cells could be useful in developing therapeutic strategies to block primary tumor progression and metastasis.
    Frontiers in Genetics 12/2014; 5:426. DOI:10.3389/fgene.2014.00426
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    ABSTRACT: 8,5' cyclopurine deoxynucleosides (cPu) are locally distorting DNA base lesions corrected by nucleotide excision repair (NER) and proposed to play a role in neurodegeneration prevalent in genetically defined Xeroderma pigmentosum (XP) patients. In the current study, purified recombinant helicases from different classifications based on sequence homology were examined for their ability to unwind partial duplex DNA substrates harboring a single site-specific cPu adduct. Superfamily (SF) 2 RecQ helicases (RECQ1, BLM, WRN, RecQ) were inhibited by cPu in the helicase translocating strand, whereas helicases from SF1 (UvrD) and SF4 (DnaB) tolerated cPu in either strand. SF2 Fe-S helicases (FANCJ, DDX11 (ChlR1), DinG, XPD) displayed marked differences in their ability to unwind the cPu DNA substrates. Archaeal Thermoplasma acidophilum XPD (taXPD), homologue to the human XPD helicase involved in NER DNA damage verification, was impeded by cPu in the non-translocating strand, while FANCJ was uniquely inhibited by the cPu in the translocating strand. Sequestration experiments demonstrated that FANCJ became trapped by the translocating strand cPu whereas RECQ1 was not, suggesting the two SF2 helicases interact with the cPu lesion by distinct mechanisms despite strand-specific inhibition for both. Using a protein trap to simulate single-turnover conditions, the rate of FANCJ or RECQ1 helicase activity was reduced 10-fold and 4.5-fold, respectively, by cPu in the translocating strand. In contrast, single-turnover rates of DNA unwinding by DDX11 and UvrD helicases were only modestly affected by the cPu lesion in the translocating strand. The marked difference in effect of the translocating strand cPu on rate of DNA unwinding between DDX11 and FANCJ helicase suggests the two Fe-S cluster helicases unwind damaged DNA by distinct mechanisms. The apparent complexity of helicase encounters with an unusual form of oxidative damage is likely to have important consequences in the cellular response to DNA damage and DNA repair.
    PLoS ONE 11/2014; 9(11):e113293. DOI:10.1371/journal.pone.0113293 · 3.53 Impact Factor


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