Article

Pathways and functions of the Werner syndrome protein

Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Mechanisms of Ageing and Development (Impact Factor: 3.51). 02/2005; 126(1):79-86. DOI: 10.1016/j.mad.2004.09.011
Source: PubMed

ABSTRACT Mutations in human WRN (also known as RECQ3) gene give rise to a rare autosomal recessive genetic disorder, Werner syndrome (WS). WS is a premature aging disease characterized by predisposition to cancer and early onset of symptoms related to normal aging including osteoporosis, ocular cataracts, graying and loss of hair, diabetes mellitus, arteriosclerosis, and atherosclerosis. This review focuses on the functional role of Werner protein (WRN) in guarding the genetic stability of cells, particularly by playing an integral role in the base excision repair, and at the telomere ends. Furthermore, in-depth biochemical investigations have significantly advanced our understanding of WRN protein regarding its binding partners and the site of protein-protein interaction. The mapping analysis of protein interaction sites in WRN for most of its binding partners have revealed a common site of protein-protein interaction in the RecQ conserved (RQC) region of WRN.

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Available from: Patricia L Opresko, Aug 03, 2015
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    • "Significantly, mutations and genes in which these mutations occur were identified for each of these syndromes. The Werner syndrome protein is a RECQ-related DNA helicase that is known to be involved in DNA repair, in addition to other cellular processes as outlined below [53]. Trichothiodystrophy is caused by point mutation in the XPD gene, which is involved in nucleotide excision repair (NER,[54]). "
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    06/2012; 3(3):260-8.
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    • "Several benzene metabolites, including HQ, have been shown to initiate oxidative DNA damage in HL60 cells (Kolachana et al., 1993). As WRN has proposed roles in BER (see Lee et al., 2005) and recombinational repair pathways (see Bachrati and Hickson, 2003), WRN may have specific functions in relation to the processing of different DNA lesions initiated by HQ. More specifically, because WRN exonuclease arrests at certain oxidative lesions (Machwe et al., 2000) and has been proposed to function as a proofreader for polymerases that lack intrinsic proofreading ability (Shevelev and Hubscher, 2002), it has been suggested that WRN may act as a sensor of oxidative damage (Von Kobbe et al., 2004). "
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    ABSTRACT: Werner syndrome (WS) is a rare autosomal progeroid disorder caused by a mutation in the gene encoding the WRN (Werner syndrome protein), a member of the RecQ family of helicases with a role in maintaining genomic stability. Genetic association studies have previously suggested a link between WRN and susceptibility to benzene-induced hematotoxicity. To further explore the role of WRN in benzene-induced hematotoxicity, we used short hairpin RNA to silence endogenous levels of WRN in the human HL60 acute promyelocytic cell line and subsequently exposed the cells to hydroquinone (HQ). Suppression of WRN led to an accelerated cell growth rate, increased susceptibility to hydroquinone-induced cytotoxicity and genotoxicity as measured by the single-cell gel electrophoresis assay, and an enhanced DNA damage response. More specifically, loss of WRN resulted in higher levels of early apoptosis, marked by increases in relative levels of cleaved caspase-7 and cleaved poly (ADP-ribose) polymerase 1, in cells treated with HQ compared with control cells. Our data suggests that WRN plays an important role in the surveillance of and protection against DNA damage induced by HQ. This provides mechanistic support for the link between WRN and benzene-induced hematotoxicity.
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    • "The role of WRN in resolving steps of recombination is supported by the observation that WRN contains an enzymatic property which unwinds Holliday junction structures. In vitro studies have demonstrated that the WRN helicase activity is able to unwind HJs through a branch migration-like activity (Constantinou et al. 2000; Shen and Loeb 2001; Bachrati and Hickson 2003; Khakhar et al. 2003 Lee et al. 2005). "
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