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Acetylation of Werner syndrome protein (WRN): relationships with DNA damage, DNA replication and DNA metabolic activities

Biogerontology volume 15, pages 347–366 (2014)Cite this article

Abstract

Loss of Werner syndrome protein function causes Werner syndrome, characterized by increased genomic instability, elevated cancer susceptibility and premature aging. Although WRN is subject to acetylation, phosphorylation and sumoylation, the impact of these modifications on WRN’s DNA metabolic function remains unclear. Here, we examined in further depth the relationship between WRN acetylation and its role in DNA metabolism, particularly in response to induced DNA damage. Our results demonstrate that endogenous WRN is acetylated somewhat under unperturbed conditions. However, levels of acetylated WRN significantly increase after treatment with certain DNA damaging agents or the replication inhibitor HU. Use of DNA repair-deficient cells or repair pathway inhibitors further increase levels of acetylated WRN, indicating that induced DNA lesions and their persistence are at least partly responsible for increased acetylation. Notably, acetylation of WRN correlates with inhibition of DNA synthesis, suggesting that replication blockage might underlie this effect. Moreover, WRN acetylation modulates its affinity for and activity on certain DNA structures, in a manner that may enhance its relative specificity for physiological substrates. Our results also show that acetylation and deacetylation of endogenous WRN is a dynamic process, with sirtuins and other histone deacetylases contributing to WRN deacetylation. These findings advance our understanding of the dynamics of WRN acetylation under unperturbed conditions and following DNA damage induction, linking this modification not only to DNA damage persistence but also potentially to replication stalling caused by specific DNA lesions. Our results are consistent with proposed metabolic roles for WRN and genomic instability phenotypes associated with WRN deficiency.

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Acknowledgments

This research was supported by grants R01AG027258 and R01AG026534 to D.K.O. and J.L., respectively, from the National Institute on Aging of the National Institutes of Health. The authors would also like to thank Dr. Amrita Machwe for critical reading of the manuscript.

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  1. Graduate Center for Toxicology, University of Kentucky College of Medicine, 356 HSRB, 1095 V.A. Drive, Lexington, KY, 40536, USA

    Enerlyn Lozada & David K. Orren

  2. Department of Medical and Research Technology, University of Maryland Medical School, Baltimore, MD, 21201, USA

    Jingjie Yi & Jianyuan Luo

  3. Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    David K. Orren

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  1. Enerlyn Lozada
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  2. Jingjie Yi
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Lozada, E., Yi, J., Luo, J. et al. Acetylation of Werner syndrome protein (WRN): relationships with DNA damage, DNA replication and DNA metabolic activities. Biogerontology 15, 347–366 (2014). https://doi.org/10.1007/s10522-014-9506-3

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Keywords

  • Progeroid syndromes
  • Genomic instability
  • DNA damage
  • DNA replication
  • Histone deacetylases