期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 23, 期 2, 页码 754-761出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.23.2.754-761.2003
关键词
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资金
- NCI NIH HHS [R01 CA091029, CA75160, CA76172, R01 CA075160, P30 CA016672, CA91029, R01 CA076172, R29 CA076172] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA091029, R29CA076172, R01CA076172, R01CA075160, P30CA016672] Funding Source: NIH RePORTER
Interstrand cross-links (ICLs) make up a unique class of DNA lesions in which both strands of the double helix are covalently joined, precluding strand opening during replication and transcription. The repair of DNA ICLs has become a focus of study since ICLs are recognized as the main cytotoxic lesion inflicted by an array of alkylating compounds used in cancer treatment. As is the case for double-strand breaks, a damage-free homologous copy is essential for the removal of ICLs in an error-free manner. However, recombination-independent mechanisms may exist to remove ICLs in an error-prone fashion. We have developed an in vivo reactivation assay that can be used to examine the removal of site-specific mitomycin C-mediated ICLs in mammalian cells. We found that the removal of the ICL from the reporter substrate could take place in the absence of undamaged homologous sequences in repair-proficient cells, suggesting a cross-link repair mechanism that is independent of homologous recombination. Systematic analysis of nucleotide excision repair mutants demonstrated the involvement of transcription-coupled nucleotide excision repair and a partial requirement for the lesion bypass DNA polymerase M encoded by the human POLH gene. From these observations, we propose the existence of a recombination-independent and mutagenic repair pathway for the removal of ICLs in mammalian cells.
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