Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance

Shigeo Oba, Joydeep Mukherjee, Wendy L. See, Russell O. Pieper

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower grade glioma and not only drive gliomagenesis but are also associated with longer patient survival and improved response to temozolomide. To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and temozolomide response. Temozolomide-sensitive parental cells exhibited DNA damage (γ-H2AX foci) and a prolonged G2cell-cycle arrest beginning three days after temozolomide (100 μmol/L, 3 hours) exposure and persisting for more than four days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell-cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell-cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly, these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established glioma cells. They were, however, associated with increased homologous recombination (HR) and could be reversed by the genetic or pharmacologic suppression of the HR DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance HR and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance. The results also suggest that inhibitors of HR may be a viable means to enhance temozolomide response in IDH1-mutant glioma.

Original languageEnglish
Pages (from-to)4836-4844
Number of pages9
JournalCancer Research
Volume74
Issue number17
DOIs
Publication statusPublished - 01-09-2014
Externally publishedYes

Fingerprint

temozolomide
Isocitrate Dehydrogenase
Homologous Recombination
DNA Damage
Glioma
Recombinational DNA Repair
Rad51 Recombinase
Survival
Cell Cycle Checkpoints
Astrocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Oba, Shigeo ; Mukherjee, Joydeep ; See, Wendy L. ; Pieper, Russell O. / Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance. In: Cancer Research. 2014 ; Vol. 74, No. 17. pp. 4836-4844.
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Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance. / Oba, Shigeo; Mukherjee, Joydeep; See, Wendy L.; Pieper, Russell O.

In: Cancer Research, Vol. 74, No. 17, 01.09.2014, p. 4836-4844.

Research output: Contribution to journalArticle

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AU - Mukherjee, Joydeep

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