Weihua Zhou, Zitong Zhao, Angelica Lin, John Yang, Jie Xu, Wilder-Romans Kari, Annabel Yang, Jing Li, Sumeet Solanki, Jennifer Speth, Natalie Walker, Andrew J Scott, Ayesha U Kothari, Yangyang Yao, Erik R Peterson, Navyateja Korimerla, Christian K Werner, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra M Obrien, Ameer L Elaimy, Sean P Ferris, Shuang G Zhao, Jann N Sarkaria, Balázs Győrffy, Shuqun Zhang, Wajd N Al-Holou, Yoshie Umemura, Meredith A Morgan, Theodore S Lawrence, Costas A Lyssiotis, Marc Peters-Golden, Yatrik M Shah, Daniel R Wahl
How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments...
April 13, 2023: bioRxiv