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HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation
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HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation
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Journal Article
HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation
2020
Overview
The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells
1
,
2
. After binding to genomic lesions, these enzymes use NAD
+
to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors
3
,
4
. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues
5
–
10
. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD
+
-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.
Assembly of a catalytic centre formed by HPF1 bound to PARP1 or PARP2 is essential for protein ADP-ribosylation after DNA damage in human cells.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/16
/ 96
/ 96/1
/ 96/106
/ 96/95
/ Animals
/ Carrier Proteins - chemistry
/ Carrier Proteins - metabolism
/ Damage
/ DNA
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ NAD
/ NMR
/ Nuclear Magnetic Resonance, Biomolecular
/ Nuclear Proteins - chemistry
/ Nuclear Proteins - metabolism
/ Poly (ADP-Ribose) Polymerase-1 - chemistry
/ Poly (ADP-Ribose) Polymerase-1 - metabolism
/ Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
/ Poly(ADP-ribose) Polymerases - chemistry
/ Poly(ADP-ribose) Polymerases - metabolism
/ Post-translational modification
/ Proteins
/ Ribose
/ Science
/ Serine
/ Switches
