2N8A

1H, 13C and 15N chemical shift assignments and solution structure for PARP-1 F1F2 domains in complex with a DNA single-strand break

Summary for 2N8A

• Entry DOI: 10.2210/pdb2n8a/pdb
• NMR Information: BMRB: 25888
• Descriptor: Poly [ADP-ribose] polymerase 1, DNA (45-MER), ZINC ION (3 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P09874
• Total number of polymer chains: 2
• Total formula weight: 38109.25

Authors

Neuhaus, D.,Eustermann, S.,Yang, J.,Wu, W. (deposition date: 2015-10-08, release date: 2015-12-02, Last modification date: 2024-05-01)

Primary citation

Eustermann, S.,Wu, W.F.,Langelier, M.F.,Yang, J.C.,Easton, L.E.,Riccio, A.A.,Pascal, J.M.,Neuhaus, D.
Structural Basis of Detection and Signaling of DNA Single-Strand Breaks by Human PARP-1.
Mol.Cell, 60:742-754, 2015

PubMed Abstract: Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1's function remained obscure; inherent dynamics of SSBs and PARP-1's multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1's signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformability of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodification in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.

PubMed: 26626479
DOI: 10.1016/j.molcel.2015.10.032

Experimental method

SOLUTION NMR