期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 19, 页码 8979-8994出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt670
关键词
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资金
- National Institutes of Health [K22 CA120049, K22 CA120049-03S1]
- American Cancer Society [IRG 58-012-51]
- Kingsley Fellowship in Medical Research
DNA sequences capable of forming triplexes are prevalent in the human genome and have been found to be intrinsically mutagenic. Consequently, a balance between DNA repair and apoptosis is critical to counteract their effect on genomic integrity. Using triplex-forming oligonucleotides to synthetically create altered helical distortions, we have determined that pro-apoptotic pathways are activated by the formation of triplex structures. Moreover, the TFIIH factor, XPD, occupies a central role in triggering apoptosis in response to triplex-induced DNA strand breaks. Here, we show that triplexes are capable of inducing XPD-independent double strand breaks, which result in the formation of gamma H2AX foci. XPD was subsequently recruited to the triplex-induced double strand breaks and co-localized with gamma H2AX at the damage site. Furthermore, phosphorylation of H2AX tyrosine 142 was found to stimulate the signaling pathway of XPD-dependent apoptosis. We suggest that this mechanism may play an active role in minimizing genomic instability induced by naturally occurring noncanonical structures, perhaps protecting against cancer initiation.
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