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 Celljournal_title
Molecular cellauthors
Dawicki-McKenna JM,Langelier MF,DeNizio JE,Riccio AA,Cao CD,Karch KR,McCauley M,Steffen JD,Black BE,Pascal JMdoi
10.1016/j.molcel.2015.10.013subject
Has Abstractpub_date
2015-12-03 00:00:00pages
755-768issue
5eissn
1097-2765issn
1097-4164pii
S1097-2765(15)00780-7journal_volume
60pub_type
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