Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway

Fengtao Su, Souparno Bhattacharya, Salim Abdisalaam, Shibani Mukherjee, Hirohiko Yajima, Yanyong Yang, Ritu Mishra, Kalayarasan Srinivasan, Subroto Ghose, David J. Chen, Steven M. Yannone, Aroumougame Asaithamby

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Faithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Herein, we report that ATR-mediated WRN phosphorylation is needed for DNA replication and repair upon replication stress. A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. The dynamic interaction between WRN and DNA is required for the suppression of new origin firing and Rad51-dependent double-stranded DNA break repair. Significantly, ATR-mediated WRN phosphorylation is critical for the suppression of chromosome breakage during replication stress. These findings reveal a unique role for WRN as a modulator of DNA repair, replication, and recombination, and link ATR-WRN signaling to the maintenance of genome stability.

Original languageEnglish (US)
Pages (from-to)46-65
Number of pages20
JournalOncotarget
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Chromosome instability
  • Gerotarget
  • Post-translational modification
  • Replication stress
  • Werner syndrome
  • Werner syndrome protein

ASJC Scopus subject areas

  • Oncology

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    Su, F., Bhattacharya, S., Abdisalaam, S., Mukherjee, S., Yajima, H., Yang, Y., Mishra, R., Srinivasan, K., Ghose, S., Chen, D. J., Yannone, S. M., & Asaithamby, A. (2016). Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway. Oncotarget, 7(1), 46-65. https://doi.org/10.18632/ONCOTARGET.6659