Rapid Detection and Signaling of DNA Damage by PARP-1

Nootan Pandey; Ben E Black

doi:10.1016/j.tibs.2021.01.014

Rapid Detection and Signaling of DNA Damage by PARP-1

Trends Biochem Sci. 2021 Sep;46(9):744-757. doi: 10.1016/j.tibs.2021.01.014. Epub 2021 Mar 3.

Authors

Nootan Pandey¹, Ben E Black²

Affiliations

¹ Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: blackbe@pennmedicine.upenn.edu.

Abstract

Poly(ADP-ribosyl) polymerase-1 (PARP-1) is an abundant ADP-ribosyl transferase that regulates various biological processes. PARP-1 is widely recognized as a first-line responder molecule in DNA damage response (DDR). Here, we review the full cycle of detecting DNA damage by PARP-1, PARP-1 activation upon DNA binding, and PARP-1 release from a DNA break. We also discuss the allosteric consequence upon binding of PARP inhibitors (PARPi) and the opportunity to tune its release from a DNA break. It is now possible to harness this new understanding to design novel PARPi for treating diseases where cell toxicity caused by PARP-1 'trapping' on DNA is either the desired consequence or entirely counterproductive.

Keywords: DNA damage response; PARPi; PARylation; poly(ADP-ribose) glycohydrolase.

Publication types

Research Support, N.I.H., Extramural
Review

MeSH terms

Biological Phenomena*
DNA Damage
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
Signal Transduction

Substances

Poly(ADP-ribose) Polymerase Inhibitors

Grants and funding

R35 GM130302/GM/NIGMS NIH HHS/United States