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

// Fengtao Su 1 , Souparno Bhattacharya 1 , Salim Abdisalaam 1 , Shibani Mukherjee 2 , Hirohiko Yajima 1,4 , Yanyong Yang 1 , Ritu Mishra 1 , Kalayarasan Srinivasan 1 , Subroto Ghose 2 , David J. Chen 1 , Steven M. Yannone 3 and Aroumougame Asaithamby 1 1 Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 2 Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA 4 Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan Correspondence to: Aroumougame Asaithamby, email: // Keywords : Werner syndrome protein, Werner syndrome, replication stress, post-translational modification,chromosome instability, Gerotarget Received : November 06, 2015 Accepted : November 23, 2015 Published : December 18, 2015 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.