Multifaceted Role of PARP1 in Maintaining Genome Stability Through Its Binding to Alternative DNA Structures

Alternative DNA structures that differ from the canonical B-form of DNA can arise from repetitive sequences and play beneficial roles in many cellular processes such as gene regulation and chromatin organization. However, they also threaten genomic stability in several ways including mutagenesis and collisions with replication and/or transcription machinery, which lead to genomic instability that is associated with human disease. Thus, the careful regulation of non-B-DNA structure formation and resolution is crucial for the maintenance of genome integrity. Several protein factors have been demonstrated to associate with alternative DNA structures to facilitate their removal, one of which is the ADP-ribose transferase (ART) PARP1 (also called ADP-ribosyltransferase diphtheria toxin-like 1 or ARTD1), a multifaceted DNA repair enzyme that recognizes single- and double-stranded DNA breaks and synthesizes chains of poly (ADP-ribose) (PAR) to recruit DNA repair proteins. It is now well appreciated that PARP1 recognizes several nucleic acid structures beyond DNA lesions, including stalled replication forks, DNA hairpins and cruciforms, R-loops, and DNA G-quadruplexes (G4 DNA). In this review, we summarize the current evidence of a direct association of PARP1 with each of these aforementioned alternative DNA structures, as well as discuss the role of PARP1 in the prevention of non-B-DNA structure-induced genetic instability. We will focus on the mechanisms of the recognition and binding by PARP1 to each alternative structure and the structure-based stimulation of PARP1 catalytic activity upon binding. Finally, we will discuss some of the outstanding gaps in the literature and offer speculative insight for questions that remain to be experimentally addressed.