The role of poly ADP-ribosylation in the first wave of DNA damage response

Abstract

Poly ADP-ribose polymerases (PARPs) catalyze massive protein poly ADP-ribosylation (PARylation) within seconds after the induction of DNA single- or double-strand breaks. PARylation occurs at or near the sites of DNA damage and promotes the recruitment of DNA repair factors via their poly ADP-ribose (PAR) binding domains. Several novel PAR-binding domains have been recently identified. Here, we summarize these and other recent findings suggesting that PARylation may be the critical event that mediates the first wave of the DNA damage response. We also discuss the potential for functional crosstalk with other DNA damage-induced post-translational modifications.

Figure 1.

Schematic representation of PAR synthesis. PARPs hydrolyze nicotinamide from NAD⁺ and covalently link the remaining ADP-ribose moieties to their substrates, forming linear or branched PAR chains. Different PAR readers recognize distinct units of the PAR chain. The PBZ motif recognizes tandem ADP-ribose. The WWE, FHA and OB domains recognize iso-ADP-ribose. The macro and BRCT domains recognize ADP-ribose. The recognition units of the RRM, PIN and PbR domains need to be identified. ADPr: ADP-ribose; iso-ADPr: iso-ADP-ribose.

Figure 2.

Schematic representation of the temporal dynamics of DDR proteins recruited to the DNA damage sites in response to laser micro-irradiation.

Figure 3.

PARP1 is a sensor for both SSBs (A) and DSBs (B). The domains within one PARP1 molecule are colored differently. ZF1-3, N-terminal zinc finger motif 1-3; BRCT, BRCT domain; WGR, WGR domain; CAT, C-terminal catalytic domain.

Figure 4.

Schematic representation of the deADP-ribosylation process. The cutting sites of each enzyme are shown by the arrows with indicated colors. ADPr: ADP-ribose.

Figure 5.

Functional interactions between DNA damage-induced PARylation and other post-translational modifications. (A) PARP1-mediated PARylation facilitates the early recruitment of DNA damage factors (e.g. NBS1, BARD1 and CHFR). (B) In response to PARylation, other post-translational modifications (e.g. phosphorylation and ubiquitination) stabilize the DDR machinery.