Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma

Thomas Ströbel, Sibylle Madlener, Serkan Tuna, Sarah Vose, Tonny Lagerweij, Thomas Wurdinger, Klemens Vierlinger, Adelheid Wöhrer, Brendan D. Price, Bruce Demple, Okay Saydam, Nurten Saydam

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number9674
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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Drug Tolerance
Glioblastoma
Recombinational DNA Repair
DNA Repair
temozolomide
DNA End-Joining Repair
DNA-(Apurinic or Apyrimidinic Site) Lyase
Pharmaceutical Preparations
Neoplasms
Phosphotransferases
Survival
DNA
Proteins

Cite this

Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. / Ströbel, Thomas; Madlener, Sibylle; Tuna, Serkan; Vose, Sarah; Lagerweij, Tonny; Wurdinger, Thomas; Vierlinger, Klemens; Wöhrer, Adelheid; Price, Brendan D.; Demple, Bruce; Saydam, Okay; Saydam, Nurten.

In: Scientific reports, Vol. 7, No. 1, 9674, 01.12.2017.

Research output: Contribution to journalArticle

Ströbel, T, Madlener, S, Tuna, S, Vose, S, Lagerweij, T, Wurdinger, T, Vierlinger, K, Wöhrer, A, Price, BD, Demple, B, Saydam, O & Saydam, N 2017, 'Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma', Scientific reports, vol. 7, no. 1, 9674. https://doi.org/10.1038/s41598-017-10013-w
Ströbel, Thomas ; Madlener, Sibylle ; Tuna, Serkan ; Vose, Sarah ; Lagerweij, Tonny ; Wurdinger, Thomas ; Vierlinger, Klemens ; Wöhrer, Adelheid ; Price, Brendan D. ; Demple, Bruce ; Saydam, Okay ; Saydam, Nurten. / Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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