XPD‐Dependent induction of apoptosis in cells with DNA containing triple helical repeats

Naturally occurring DNA sequences capable of forming H‐DNA (triplexes) are found in the human genome as frequently as 1 in every 50,000 base pairs. These sequences, typically located in promoters and exons have been found to be intrinsically mutagenic. To counteract the potentially devastating effects of altered helical structures on genomic integrity, an intricate balance between DNA repair and apoptosis is critical. Studies have determined that triplex formation is recognized and repaired as DNA damage by the nucleotide excision repair pathway. In studies that measured induction of repair synthesis, we determined that synthetically generated triplexes created a helical distortion that strongly provoked XPA‐dependent DNA repair. However, when excessive helical‐distorting damage induced by multiple triplex structures overwhelmed the cell's capacity for effective repair, pro‐apoptotic pathways were activated. The TFIIH factor, XPD has been implicated in our studies to occupy a central role in triggering apoptosis in response to excessive H‐DNA induced damage. The maintenance of this mechanism may be of central importance for avoiding induction of mutations and progression to cancer.