Torin2 suppresses ionizing radiation-induced DNA damage repair

Durga Udayakumar, Raj K. Pandita, Nobuo Horikoshi, Yan Liu, Qingsong Liu, Kwok Kin Wong, Clayton R. Hunt, Nathanael S. Gray, John D. Minna, Tej K. Pandita, Kenneth D. Westover

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have been developed based on its central role in sensing growth factor and nutrient levels to regulate cellular metabolism. However, its ATP-binding site closely resembles other phosphatidylinositol 3-kinase-related kinase (PIKK) family members, resulting in reactivity with these targets that may also be therapeutically useful. The ATP-competitive mTOR inhibitor, Torin2, shows biochemical activity against the DNA repair-associated proteins ATM, ATR and DNA-PK, which raises the possibility that Torin2 and related compounds might radiosensitize cancerous tumors. In this study Torin2 was also found to enhance ionizing radiation-induced cell killing in conditions where ATM was dispensable, confirming the requirement for multiple PIKK targets. Moreover, Torin2 did not influence the initial appearance of γ-H2AX foci after irradiation but significantly delayed the disappearance of radiation-induced γ-H2AX foci, indicating a DNA repair defect. Torin2 increased the number of radiation-induced S-phase specific chromosome aberrations and reduced the frequency of radiation-induced CtIP and Rad51 foci formation, suggesting that Torin2 works by blocking homologous recombination (HR)-mediated DNA repair resulting in an S-phase specific DNA repair defect. Accordingly, Torin2 reduced HR-mediated repair of I-Sce1-induced DNA damage and contributed to replication fork stalling. We conclude that radiosensitization of tumor cells by Torin2 is associated with disrupting ATR- and ATM-dependent DNA damage responses. Our findings support the concept of developing combination cancer therapies that incorporate ionizing radiation therapy and Torin2 or compounds with similar properties.

Original languageEnglish (US)
Pages (from-to)527-538
Number of pages12
JournalRadiation Research
Volume185
Issue number5
DOIs
StatePublished - May 1 2016

Fingerprint

Ionizing Radiation
DNA Repair
ionizing radiation
Phosphatidylinositol 3-Kinase
DNA Damage
Recombinational DNA Repair
deoxyribonucleic acid
Sirolimus
Radiation
damage
S Phase
asynchronous transfer mode
Phosphotransferases
Adenosine Triphosphate
Ataxia Telangiectasia Mutated Proteins
Neoplasms
adenosine triphosphate
Chromosome Aberrations
Intercellular Signaling Peptides and Proteins
inhibitors

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Torin2 suppresses ionizing radiation-induced DNA damage repair. / Udayakumar, Durga; Pandita, Raj K.; Horikoshi, Nobuo; Liu, Yan; Liu, Qingsong; Wong, Kwok Kin; Hunt, Clayton R.; Gray, Nathanael S.; Minna, John D.; Pandita, Tej K.; Westover, Kenneth D.

In: Radiation Research, Vol. 185, No. 5, 01.05.2016, p. 527-538.

Research output: Contribution to journalArticle

Udayakumar, D, Pandita, RK, Horikoshi, N, Liu, Y, Liu, Q, Wong, KK, Hunt, CR, Gray, NS, Minna, JD, Pandita, TK & Westover, KD 2016, 'Torin2 suppresses ionizing radiation-induced DNA damage repair', Radiation Research, vol. 185, no. 5, pp. 527-538. https://doi.org/10.1667/RR14373.1
Udayakumar D, Pandita RK, Horikoshi N, Liu Y, Liu Q, Wong KK et al. Torin2 suppresses ionizing radiation-induced DNA damage repair. Radiation Research. 2016 May 1;185(5):527-538. https://doi.org/10.1667/RR14373.1
Udayakumar, Durga ; Pandita, Raj K. ; Horikoshi, Nobuo ; Liu, Yan ; Liu, Qingsong ; Wong, Kwok Kin ; Hunt, Clayton R. ; Gray, Nathanael S. ; Minna, John D. ; Pandita, Tej K. ; Westover, Kenneth D. / Torin2 suppresses ionizing radiation-induced DNA damage repair. In: Radiation Research. 2016 ; Vol. 185, No. 5. pp. 527-538.
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