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: 3.4). 02/2005; 126(1):79-86. DOI: 10.1016/j.mad.2004.09.011
Source: PubMed


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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    • "We found that Polλ bound well to GST–WRN949–1432 and GST–WRN500–946, but not to GST–WRN51–499 or to GST alone (Supplementary Figure S7). These results indicated that Polλ interacted with the helicase domain of WRN (amino acids 500–946) as well as with the C-terminal region of WRN, which contains winged-helix domain, a binding site of a number of other proteins shown to interact with WRN (28). "
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    ABSTRACT: Reactive oxygen species constantly generated as by-products of cellular metabolism readily attack genomic DNA creating mutagenic lesions such as 7,8-dihydro-8-oxo-guanine (8-oxo-G) that promote aging. 8-oxo-G:A mispairs arising during DNA replication are eliminated by base excision repair initiated by the MutY DNA glycosylase homologue (MUTYH). Here, by using formaldehyde crosslinking in mammalian cell extracts, we demonstrate that the WRN helicase/exonuclease defective in the premature aging disorder Werner syndrome (WS) is recruited to DNA duplex containing an 8-oxo-G:A mispair in a manner dependent on DNA polymerase λ (Polλ) that catalyzes accurate DNA synthesis over 8-oxo-G. Similarly, by immunofluorescence, we show that Polλ is required for accumulation of WRN at sites of 8-oxo-G lesions in human cells. Moreover, we show that nuclear focus formation of WRN and Polλ induced by oxidative stress is dependent on ongoing DNA replication and on the presence of MUTYH. Cell viability assays reveal that depletion of MUTYH suppresses the hypersensitivity of cells lacking WRN and/or Polλ to oxidative stress. Biochemical studies demonstrate that WRN binds to the catalytic domain of Polλ and specifically stimulates DNA gap filling by Polλ over 8-oxo-G followed by strand displacement synthesis. Our results suggest that WRN promotes long-patch DNA repair synthesis by Polλ during MUTYH-initiated repair of 8-oxo-G:A mispairs.
    Nucleic Acids Research 06/2012; 40(17):8449-59. DOI:10.1093/nar/gks648 · 9.11 Impact Factor
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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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    ABSTRACT: Aging is a process that involves all organs and tissues of the human organism. Cells and tissues are impacted by aging in differing degrees, depending on their regenerative potential and sensitivity to outside stimuli. In this review, we discuss the potential role of adult stem cells in the aging process, and the new results that support the role of stem cells in the aging process. Finally, we discuss new evidence from progeroid syndromes that supports the stem cell hypothesis of aging.
    Aging and Disease 06/2012; 3(3):260-8. · 3.07 Impact Factor
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    • "WRN is a multi-functional protein potentially involved in many processes in DNA metabolism [26]. How WRN protein is regulated in response to DNA damage is of great interest. "
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    ABSTRACT: WRN is a multi-functional protein involving DNA replication, recombination and repair. WRN acetylation has been demonstrated playing an important role in response to DNA damage. We previously found that WRN acetylation can regulate its enzymatic activities and nuclear distribution. Here, we investigated the factors involved in WRN acetylation and found that CBP and p300 are the only major acetyltransferases for WRN acetylation. We further identified 6 lysine residues in WRN that are subject to acetylation. Interestingly, WRN acetylation can increase its protein stability. SIRT1-mediated deacetylation of WRN reverses this effect. CBP dramatically increases the half-life of wild type WRN, while mutation of these 6 lysine residues (WRN-6KR) abrogates this increase. We further found that WRN stability is regulated by the ubiquitination pathway and WRN acetylation by CBP significantly reduces its ubiquitination. Importantly, we found that WRN is strongly acetylated and stabilized in response to mitomycin C (MMC) treatment. H1299 cells stably expressing WRN-6KR, which mimics unacetylated WRN, display significantly higher MMC sensitivity compared with the cells expressing wild-type WRN. Taken together, these data demonstrate that WRN acetylation regulates its stability and has significant implications regarding the role of acetylation on WRN function in response to DNA damage.
    PLoS ONE 04/2010; 5(4):e10341. DOI:10.1371/journal.pone.0010341 · 3.23 Impact Factor
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