title: Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway.
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.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Fengtao
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Souparno
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdisalaam
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Shibani
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Yajima
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Yanyong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kalayarasan
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Yannone
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
chemical_list: D014452:Ubiquitins; D012694:Serine; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D005090:Exodeoxyribonucleases; D046988:Proteasome Endopeptidase Complex; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
keywords: Gerotarget; Werner syndrome; Werner syndrome protein; chromosome instability; post-translational modification; replication stress