XPD-dependent activation of apoptosis in response to triplex-induced DNA damage

Nucleic Acids Res. 2013 Oct;41(19):8979-94. doi: 10.1093/nar/gkt670. Epub 2013 Aug 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA Repair
  • DNA* / chemistry
  • Genomic Instability
  • Mice
  • Xeroderma Pigmentosum Group D Protein / metabolism*
  • Xeroderma Pigmentosum Group D Protein / physiology

Substances

  • triplex DNA
  • DNA
  • Xeroderma Pigmentosum Group D Protein