TY - JOUR
T1 - Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
AU - Su, Fengtao
AU - Bhattacharya, Souparno
AU - Abdisalaam, Salim
AU - Mukherjee, Shibani
AU - Yajima, Hirohiko
AU - Yang, Yanyong
AU - Mishra, Ritu
AU - Srinivasan, Kalayarasan
AU - Ghose, Subroto
AU - Chen, David J.
AU - Yannone, Steven M.
AU - Asaithamby, Aroumougame
N1 - Publisher Copyright:
© 2015. Oncotarget.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Chromosome instability
KW - Gerotarget
KW - Post-translational modification
KW - Replication stress
KW - Werner syndrome
KW - Werner syndrome protein
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U2 - 10.18632/ONCOTARGET.6659
DO - 10.18632/ONCOTARGET.6659
M3 - Article
C2 - 26695548
AN - SCOPUS:85020170770
SN - 1949-2553
VL - 7
SP - 46
EP - 65
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -