The comings and goings of PARP-1 in response to DNA damage

Abstract

Poly(ADP-ribose) polymerase (PARP) enzymes are broadly involved in the cellular response to DNA damage. PARP-1 is the chief human PARP enzyme involved in the DNA damage response, acting as a first responder that detects DNA strand breaks, and contributes to repair pathway choice and the efficiency of repair through modulation of chromatin structure and through interaction with and modification of a multitude of DNA repair factors. This perspective summarizes our knowledge of PARP-1 involvement in DNA repair pathways, and highlights recent structural and functional data regarding the activation of PARP-1 upon detecting DNA damage, and the release and trapping of PARP-1 at sites of DNA damage.

Keywords: DNA damage response; PARP; Poly(ADP-ribose).

Figure 1.. PARP-1 detecting DNA damage and primed for poly(ADP-ribose) production

Human PARP-1 domain names and organization, and a structural model for PARP-1 interaction with single-strand break DNA damage. PARP-1 binding to the ends of DNA strand break damage is achieved through coordinated action of two zinc finger domains, Zn1 and Zn2, located at the N-terminus of the protein. The Zn1 domain binds to the side of the DNA break with a terminal 5’ strand (5’ end), and the Zn2 domain binds to the side of the DNA break with a terminal 3’ strand (3’ end). A structurally unrelated third zinc binding domain, Zn3, and the WGR (Trp-Gly-Arg) domain also make contacts with DNA. The catalytic domain (CAT) is composed of an ADP-ribosyl transferase (ART) fold and a helical subdomain (HD). The linker residues (each residue represented by an individual sphere) and the BRCT (BRCA1 C-terminus) domain were manually positioned based on linker lengths and the domain termini. The NAD⁺ binding site is noted. The combined crystallographic and NMR model is shown in two orientations that are related by an approximately 90-degree rotation about a vertical axis in the plane of the page. The left view highlights the structure of the DNA break and PARP-1/DNA contacts, with the CAT domain and the BRCT in the background. The right view highlights the HD contacts with the domains that are assembled on DNA.