The role of WRN in DNA repair is affected by post-translational modifications

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). 02/2007; 128(1):50-7. DOI: 10.1016/j.mad.2006.11.010
Source: PubMed


Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by genomic instability. WRN gene encodes one of the RecQ helicase family proteins, WRN, which has ATPase, helicase, exonuclease and single stranded DNA annealing activities. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA repair, replication and recombination. The role of WRN in these pathways can be modulated by its post-translational modifications in response to DNA damage. Here, we review the functional consequences of post-translational modifications on WRN as well as specific DNA repair pathways where WRN is involved and discuss how these modifications affect DNA repair pathways.

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    • "Posttranslational modification can regulate protein-protein interaction, modulate enzymatic activities, and influence cellular localization and protein stability [13]. WRN can be acetylated in response to various DNA damaging agents [14]–[17]. "
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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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    • "The associations of WRN with particular proteins and structures are all seemingly consistent with an importance of oxidative DNA damage and telomere maintenance to longevity, again suggesting that the locale for the significant damage may be in the unusual DNA structures found in telomeres. In that regard it is of interest that WRN-deficient mammalian cells are notably sensitive to 4-nitroquinoline-1-oxide (a hallmark of WS), and that this carcinogen reacts strongly with the B-Z junctions at the ends of Z-DNA structures (Rodolfo et al., 1994) The operation of WRN in its various roles may be modulated through post-translational processing of the protein (Kusumoto et al., 2007). Post-translational processing is an emerging theme in the discovery of mechanisms that coordinate the essential processes of DNA replication, recombination and repair (Hanawalt, 2007), and the study of such processing may offer further clues to the complexities of ageing. "

    Mechanisms of Ageing and Development 07/2008; 129(7-8):503-5. DOI:10.1016/j.mad.2008.03.007 · 3.40 Impact Factor
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    • "We found that WS cells exhibited a dramatically long delay in repair protein recruitment. A possible explanation may be the fact that RecQ helicases, one of which is the protein coded by the WRN gene, were shown (Otterlei et al., 2006; Kusumoto et al., 2007) to interact with other molecular factors involved in homologous recombination, which is one mechanism of DNA DSB repair. We are tempted to speculate that the absence of WRN protein might impair the recruitment dynamics of other factors involved, despite undisturbed γ-H2AX signaling. "
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    ABSTRACT: Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age-dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage-induced foci of phosphorylated histone H2AX (gamma-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous gamma-H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of gamma-H2AX foci than those taken from normal donors of comparable age. Further increases in gamma-H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to gamma-H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of gamma-H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of gamma-H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging.
    Aging cell 02/2008; 7(1):89-100. DOI:10.1111/j.1474-9726.2007.00354.x · 6.34 Impact Factor
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