Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability

Abstract

Repetitive genomic sequences can adopt a number of alternative DNA structures that differ from the canonical B-form duplex (i.e. non-B DNA). These non-B DNA-forming sequences have been shown to have many important biological functions related to DNA metabolic processes; for example, they may have regulatory roles in DNA transcription and replication. In addition to these regulatory functions, non-B DNA can stimulate genetic instability in the presence or absence of DNA damage, via replication-dependent and/or replication-independent pathways. This review focuses on the interactions of non-B DNA conformations with DNA repair proteins and how these interactions impact genetic instability.

Keywords: DNA repair; DNA replication; DNA structure; Genetic instability; Transcription.

Figure 1

Non-B DNA structures. (A) Cruciform DNA formed at inverted repeats, (B) left-handed Z-DNA formed at alternating purine-pyrimidine sequences, (C) intermolecular triplex H-DNA formed at mirror repeat symmetric polypurine/polypyrimidine regions, (D) G-quadruplex (tetraplex) DNA formed at sequences containing at least four runs of three or more guanines, and (E) Slipped DNA formed by misalignment of simple repeats. From reference [50] with permission.

Figure 2

Schematic of the human c-MYC gene promoter and clusters of sequences with the potential to adopt non-B DNA structures. The alternative promoters P0, P1, P2, and Exon 1 are shown. Within a region of 400 bp surrounding P0, there are clusters of non-B DNA-forming sequences, including four Z-DNA-forming sequences [92] (red); two H-DNA-forming sequences [39] (black); and one G-quadruplex-forming sequence [37] (blue). The G-quadruplex and H-DNA-forming sequences overlap each other.