title: XPD-dependent activation of apoptosis in response to triplex-induced DNA damage.
abstract: 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 γH2AX foci. XPD was subsequently recruited to the triplex-induced double strand breaks and co-localized with γH2AX 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.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Meetu
authors.initials: M
authors.lastname: Kaushik Tiwari
authors.forename: Faye A
authors.initials: FA
authors.lastname: Rogers
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D051379:Mice; D051759:Xeroderma Pigmentosum Group D Protein / Q000378:metabolism* / Q000502:physiology
chemical_list: C051802:triplex DNA; D004247:DNA; D051759:Xeroderma Pigmentosum Group D Protein
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