2. Academic Validation
  3. A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells

A PARP14/TARG1-Regulated RACK1 MARylation Cycle Drives Stress Granule Dynamics in Ovarian Cancer Cells

  • bioRxiv. 2024 Sep 4:2023.10.13.562273. doi: 10.1101/2023.10.13.562273.
Sridevi Challa 1 2,  Tulip Nandu 1,  Hyung Bum Kim 1 3,  Xuan Gong 1 4,  Charles W Renshaw 1,  Wan-Chen Li 5,  Xinrui Tan 1 6,  Marwa W Aljardali 1,  Cristel V Camacho 1 6,  Jin Chen 1 5,  W Lee Kraus 1 3 6
Affiliations

Affiliations

  • 1 Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Current address: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637.
  • 3 Graduate Program in Genetics, Development, and Disease, Graduate School of Biomedical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Current address: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105.
  • 5 Altos Labs, Bay Area Institute of Science, Redwood City, CA 94403.
  • 6 Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 37873085 DOI: 10.1101/2023.10.13.562273
Abstract

Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component of the ribosome, is MARylated on three acidic residues by the mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian Cancer cells. MARylation of RACK1 is required for stress granule formation and promotes the colocalization of RACK1 in stress granules with G3BP1, eIF3η, and 40S ribosomal proteins. In parallel, we observed reduced translation of a subset of mRNAs, including those encoding key Cancer regulators (e.g., Akt). Treatment with a PARP14 Inhibitor or mutation of the sites of MARylation on RACK1 blocks these outcomes, as well as the growth of ovarian Cancer cells in culture and in vivo. To re-set the system after prolonged stress and recovery, the ADP-ribosyl hydrolase TARG1 deMARylates RACK1, leading to the dissociation of the stress granules and the restoration of translation. Collectively, our results demonstrate a therapeutically targetable pathway that controls stress granule assembly and disassembly in ovarian Cancer cells.

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