The Role of Poly(ADP-ribose) Polymerase 1 in Nuclear and Mitochondrial Base Excision Repair

Abstract

Poly(ADP-ribose) (PAR) Polymerase 1 (PARP-1), also known as ADP-ribosyl transferase with diphtheria toxin homology 1 (ARTD-1), is a critical player in DNA damage repair, during which it catalyzes the ADP ribosylation of self and target enzymes. While the nuclear localization of PARP-1 has been well established, recent studies also suggest its mitochondrial localization. In this review, we summarize the differences between mitochondrial and nuclear Base Excision Repair (BER) pathways, the involvement of PARP-1 in mitochondrial and nuclear BER, and its functional interplay with other BER enzymes.

Keywords: DNA repair; PARP-1; nuclear and mitochondrial localization.

Figure 1

PARP-1 domain layout and arrangement in the DNA-bound form. (A) Cartoon representation of the six PARP-1 domains, connected by flexible linkers (dotted lines). (B) Cartoon representation of PARP-1:DNA complex, using a single-nucleotide-gapped DNA. Zn2 binds the 3′ end of the gap, while Zn1 binds the 5′ end. Zn1 serves as a scaffold for the assembly of the remaining domains in the appropriate orientation for catalytic activation.

Figure 2

NAD+ molecule and its position in the PARP-1 active site. Left: Chemical structure of NAD+, with the two ribose moieties labeled as described in the text. Right: Zoomed-in view of a NAD+-analogue (benzamide adenine dinucleotide) bound to the PARP-1 active site (PDB: 6BHV). The H-Y-E triad of PARP-1 is shown in plum.

Figure 3

Cartoon depicting the five basic steps of BER. The enzymes responsible for steps 1 and 2 are shared between the two organelles, but the pathways diverge at step 3, during which the nucleus utilizes a traditional dRP lyase, while mitochondria use an exonuclease to remove the dRP. Steps 4 and 5 are chemically the same between the two compartments but carried out by different enzymes or enzyme complexes.

Figure 4

Working model for PARP-1 involvement during mtLP-BER.