The role of ADP-ribosylation in regulating DNA double-strand break repair

Abstract

ADP-ribosylation is the post translational modification of proteins catalysed by ADP-ribosyltransferases (ARTs). ADP-ribosylation has been implicated in a wide variety of cellular processes including cell growth and differentiation, apoptosis and transcriptional regulation. Perhaps the best characterised role, however, is in DNA repair and genome stability where ADP-ribosylation promotes resolution of DNA single strand breaks. Although ADP-ribosylation also occurs at DNA double strand breaks (DSBs), which ARTs catalyse this reaction and the molecular basis of how this modification regulates their repair remains a matter of debate. Here we review recent advances in our understanding of how ADP-ribosylation regulates DSB repair. Specifically, we highlight studies using the genetic model organism Dictyostelium, in addition to vertebrate cells that identify a third ART that accelerates DSB repair by non-homologous end-joining through promoting the interaction of repair factors with DNA lesions. The implications of these data with regards to how ADP-ribosylation regulates DNA repair and genome stability are discussed.

Figure 1

Domain organization of Dictyostelium ART orthologs. Dictyostelium open reading frames that contain a putative ART catalytic domain are illustrated. Putative protein domains were identified by IntroPro on dictyBase.org and are indicated by the colored boxes. The Zf domain is proposed to confer DNA binding function. The pADR1 domain has unknown function but contains the recently identified ZF3, which transmits the DNA binding signal to the catalytic domain to achieve activation. WGR domains are putative nucleic acid binding domains with possible RNA binding capacity. The regulatory domain has been shown to increase the catalytic activity of proteins that contain it and may be involved in regulating ADP-ribose branching activity. The 14-3-3, WWE, vWFA BRCT (Breast cancer suppressor protein-1 C-terminal), Ankryin repeat and VIT domains are all thought to be involved in mediating protein-protein interactions. U-box domains are salt bridge- and hydrogen bond-stabilized domains found in E3 ubiquitin ligases. CCHH zinc fingers are putative DNA/RNA binding motifs. The macrodomain is a PAR binding motif. The catalytic domain may confer PARP catalytic activity and contains the highly conserved NAD⁺ binding signature.