Ape1 Guides DNA Repair Pathway Choice That is Associated with Drug Tolerance in Glioblastoma

Overview

Journal Sci Rep

Specialty Science

Date 2017 Aug 31

PMID 28852018

Citations 18

Authors

Thomas Strobel

Sibylle Madlener

Serkan Tuna

Sarah Vose

Tonny Lagerweij

Thomas Wurdinger

Klemens Vierlinger

Adelheid Wohrer

Brendan D Price

Bruce Demple

Okay Saydam

Nurten Saydam

Affiliations

Soon will be listed here.

Abstract

Ape1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells. Suppression of Ape1/Chk2 signaling in glioblastoma cells facilitates alternative means of damage site recruitment of HR proteins as part of a genomic defense system. Through targeting "HR-addicted" temozolomide-resistant glioblastoma cells via a chemical inhibitor of Rad51, we demonstrated that targeting HR is a promising strategy for glioblastoma therapy. Our study uncovers a critical role for Ape1 in DNA repair pathway choice, and provides a mechanistic understanding of DNA repair-supported chemoresistance in glioblastoma cells.

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