PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain.

Abstract:

:Poly(ADP-ribose) polymerase-1 (PARP-1) creates the posttranslational modification PAR from substrate NAD(+) to regulate multiple cellular processes. DNA breaks sharply elevate PARP-1 catalytic activity to mount a cell survival repair response, whereas persistent PARP-1 hyperactivation during severe genotoxic stress is associated with cell death. The mechanism for tight control of the robust catalytic potential of PARP-1 remains unclear. By monitoring PARP-1 dynamics using hydrogen/deuterium exchange-mass spectrometry (HXMS), we unexpectedly find that a specific portion of the helical subdomain (HD) of the catalytic domain rapidly unfolds when PARP-1 encounters a DNA break. Together with biochemical and crystallographic analysis of HD deletion mutants, we show that the HD is an autoinhibitory domain that blocks productive NAD(+) binding. Our molecular model explains how PARP-1 DNA damage detection leads to local unfolding of the HD that relieves autoinhibition, and has important implications for the design of PARP inhibitors.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Dawicki-McKenna JM,Langelier MF,DeNizio JE,Riccio AA,Cao CD,Karch KR,McCauley M,Steffen JD,Black BE,Pascal JM

doi

10.1016/j.molcel.2015.10.013

subject

Has Abstract

pub_date

2015-12-03 00:00:00

pages

755-768

issue

5

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(15)00780-7

journal_volume

60

pub_type

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