12/6/2023 0 Comments Western blot results wernerWRN is unique among all RecQ helicases because of its N-terminal 3’ to 5’ exonuclease activity. WRN belongs to the RecQ DNA helicase family. These data indicate that the protein defective in WS, Werner syndrome protein (WRN), plays a role in genome stability maintenance pathways however, the exact molecular contribution of WRN to the suppression of genomic instability is unclear. Moreover, WS cells display a prolonged S-phase, impaired replication fork progression, and unstable replication forks. Furthermore, WS cells are hypersensitive to several types of DNA damaging agents including 4-nitroquinoline-1-oxide, cross-linking agents (such as mitomycin C and cisplatin), camptothecin, and hydroxyurea. Primary cells derived from WS patients exhibit elevated levels of chromosomal translocations, inversions, and large deletions with a high spontaneous mutation rate. Werner syndrome (WS) is a rare hereditary disease characterized by the premature onset of aging and a predisposition to a broad spectrum of rare cancers. 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. Significantly, ATR-mediated WRN phosphorylation is critical for the suppression of chromosome breakage during replication stress. The dynamic interaction between WRN and DNA is required for the suppression of new origin firing and Rad51-dependent double-stranded DNA break repair. 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. A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. Herein, we report that ATR-mediated WRN phosphorylation is needed for DNA replication and repair upon replication stress. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Received: NovemAccepted: NovemPublished: DecemAbstractįaithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. Keywords: Werner syndrome protein, Werner syndrome, replication stress, post-translational modification,chromosome instability, Gerotarget Yannone 3 and Aroumougame Asaithamby 1ġ Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USAĢ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USAģ Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California, USAĤ Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan 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.
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