PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis
Highlights
► PARP-1 zinc finger domains recognize exposed nucleotide bases as a DNA damage signal. ► The modular domain architecture of PARP-1 collapses onto DNA damage as a monomer. ► Interdomain communication is critical to PARP-1 activation in response to DNA damage. ► A destabilized PARP-1 catalytic domain has increased poly(ADP-ribosyl)ation activity.
Introduction
Poly(ADP-ribose) is a reversible posttranslational modification synthesized from NAD+ by poly(ADP-ribose) polymerases (PARPs), most commonly in response to cellular stress signals such as DNA damage. The most abundant PARP enzyme in cells, PARP-1 creates long and branched poly(ADP-ribose) covalently attached onto target proteins involved in gene transcription, DNA damage repair, and cell death signaling (reviewed in [1]). Owing to PARP-1 involvement in DNA damage repair, inhibitors of PARP-1 are being actively pursued for the treatment of cancer (reviewed in [2]). The primary target for PARP-1 mediated poly(ADP-ribosyl)ation is PARP-1 itself, an activity termed automodification. Several other nuclear targets are modified by PARP-1 (reviewed in [3]); however the mechanism for PARP-1 substrate selection is not well understood. PARP-1 catalytic activity is chiefly regulated through its interaction with DNA damage. Binding to DNA strand breaks elevates the PAR synthesis activity of PARP-1 over 500-fold above basal levels of DNA-independent activity. DNA-dependent PARP-1 automodification is an immediate and robust cellular response to DNA damage that contributes to the recruitment of DNA repair and chromatin remodeling factors to sites of DNA breaks [4, 5, 6, 7]. Recent structural studies highlighted in this article have begun to establish the physical basis for PARP-1 structure-specific detection of DNA breaks, and the mechanism for DNA damage-dependent activation of PARP-1 catalytic activity.
Section snippets
PARP-1 ‘beads-on-a-string’ architecture
PARP-1 has a modular architecture with DNA binding, catalytic, and regulatory functions distributed among six independently folded domains (Figure 1a). Structures of each of the individual domains of PARP-1 in the absence of DNA have been determined (Figure 1b) [8•, 9•, 10•, 11, 12] (RIKEN, Structural Genomics Consortium). Located at the PARP-1 N-terminus, two homologous zinc finger domains, Zn1 and Zn2, recognize particular DNA structures, rather than specific DNA sequences [8•, 13•, 14, 15, 16
DNA damage detection by PARP-like zinc fingers
The structure of a PARP-like DNA binding zinc finger was first determined for the homologous N-terminal zinc finger domain of DNA ligase III [42], where it serves a nick sensing function [43, 44]. The structural basis for DNA strand break detection has recently come from crystal structures of the human PARP-1 zinc fingers in complex with different models of DNA damage. The individual zinc fingers of human PARP-1, Zn1 and Zn2 were each crystallized in complex with DNA double strand breaks [13•].
DNA damage-induced PARP-1 interdomain communication
The crystal structure of PARP-1 essential domains (Zn1, Zn3, WGR-CAT) bound to a DNA double-strand break has provided the first views of how the multiple domains of PARP-1 assemble on DNA to form the active enzyme (Figure 3a) [41••]. This study has taken advantage of the fact that the Zn2 and BRCT domains are not required for DNA-dependent activity on double-strand breaks [13•, 41••, 45] and that PARP-1 activity can be reconstituted by mixing the isolated Zn1, Zn3 and WGR-CAT fragments with DNA
Coupling DNA damage detection to catalytic activity
Upon binding to a DNA break, PARP-1 domains collapse together and establish interdomain contacts that collectively distort the structure of HD when compared to HD structures determined for isolated CAT domains [41••]. The most prominent change in HD structure occurs near the interface with WGR, in the region surrounding αC (Figure 3a). In CAT structures determined in the absence of DNA and regulatory domains, αC forms an interface with αF and αB and contributes Leu698 and Leu701 to the
Remaining questions and challenges
The modular domain architecture has challenged structural analysis of PARP-1, but the divide and conquer approach has provided key insights into PARP-1 mechanism of action that are consistent with biochemical analysis of the full-length protein. Nonetheless, a structure of full-length PARP-1 bound to DNA damage will build on our understanding of how the domains of PARP-1 assemble and communicate. For example, the BRCT domain is not strictly required for DNA damage-dependent activity, but its
Conclusion
The structural biology of poly(ADP-ribose) signaling has made important advances over the past several years. In addition to the structures highlighted in this review, we have recently seen the first structures of poly(ADP-ribose) glycohydrolase (PARG) enzymes that reverse the modification [53••, 54•, 55•], protein modules that recognize the modification (WWE [56, 57] and PBZ [58, 59, 60, 61]), catalytic domains from additional PARP family enzymes [30, 32, 34], and the regulatory ankyrin
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Research in the Pascal laboratory is supported by the NIH (GM087282) and the American Cancer Society (RSG0918301DMC).
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