Post-transcriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors.

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Post-transcriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors.

Cancer Res. 2017 Jul 07;:

Authors: Chand SN, Zarei M, Schiewer MJ, Kamath AR, Romeo C, Lal S, Cozzitorto JA, Nevler A, Scolaro L, Londin E, Jiang W, Meisner-Kober N, Pishvaian MJ, Knudsen KE, Yeo CJ, Pascal JM, Winter JM, Brody JR

Abstract
The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3' untranslated region (UTR). HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP1 protein binds and post-translationally modifies HuR in PARPi-treated PDA cells. In a mouse xenograft model of human PDA, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared to PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies.

PMID: 28687616 [PubMed - as supplied by publisher]

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