The yin and yang of repair mechanisms in DNA structure-induced genetic instability

Abstract

DNA can adopt a variety of secondary structures that deviate from the canonical Watson-Crick B-DNA form. More than 10 types of non-canonical or non-B DNA secondary structures have been characterized, and the sequences that have the capacity to adopt such structures are very abundant in the human genome. Non-B DNA structures have been implicated in many important biological processes and can serve as sources of genetic instability, implicating them in disease and evolution. Non-B DNA conformations interact with a wide variety of proteins involved in replication, transcription, DNA repair, and chromatin architectural regulation. In this review, we will focus on the interactions of DNA repair proteins with non-B DNA and their roles in genetic instability, as the proteins and DNA involved in such interactions may represent plausible targets for selective therapeutic intervention.

Figure 1. Schematic diagram of DNA conformations

(A) Canonical B-DNA; (B) intra-molecular triplex , H-DNA; (C) left-handed Z-DNA; (D) cruciform; (E) hairpin (left) and slippage loop (right); (F) G-quadruplex.

Figure 2. DNA damage/repair and non-B DNA conformation-induced genetic instability

A repetitive sequence in the B-form is unwound from the histone core during DNA metabolism, e.g., DNA replication, transcription, or repair (step 1), and an altered DNA secondary structure is formed at the repetitive sequence (here shown as a Z-DNA structure). The non-B conformation can alter nucleosome reassembly, and may result in chromatin remodeling in nearby regions (step 2). The altered DNA structure can affect DNA damage and repair activities (step 3), and interfere with DNA replication (step 4). DNA repair proteins can recognize, bind to, and process the non-B DNA conformation, resulting in either melting of the DNA conformation (step 5) or to the formation DSBs eventually leading to deletion and/or translocation events (step 6).