NASA Logo

NTRS

NTRS - NASA Technical Reports Server

Back to Results
Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutantsThe radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.
Document ID
20040112649
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
External Source(s)
Authors
Asaad, N. A.
(Jefferson Medical College Philadelphia, Pennsylvania 19107, United States)
Zeng, Z. C.
Guan, J.
Thacker, J.
Iliakis, G.
Date Acquired
August 21, 2013
Publication Date
November 23, 2000
Publication Information
Publication: Oncogene
Volume: 19
Issue: 50
ISSN: 0950-9232
Subject Category
Aerospace Medicine
Funding Number(s)
CONTRACT_GRANT: 2RO1 CA42026
CONTRACT_GRANT: P30-CA56036
CONTRACT_GRANT: 56706
Distribution Limits
Public
Copyright
Other
Keywords
NASA Discipline Radiation Health
Non-NASA Center

Available Downloads

There are no available downloads for this record.
No Preview Available