PARP trapping is governed by the PARP inhibitor dissociation rate constant

Angelica A Gopal; Bianca Fernandez; Justin Delano; Ralph Weissleder; J Matthew Dubach

doi:10.1016/j.chembiol.2023.12.019

PARP trapping is governed by the PARP inhibitor dissociation rate constant

Cell Chem Biol. 2024 Jan 20:S2451-9456(23)00476-2. doi: 10.1016/j.chembiol.2023.12.019. Online ahead of print.

Authors

Angelica A Gopal¹, Bianca Fernandez¹, Justin Delano¹, Ralph Weissleder², J Matthew Dubach³

Affiliations

¹ Institute for Innovation in Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
² Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
³ Institute for Innovation in Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address: dubach.matt@mgh.harvard.edu.

PMID: 38262416
DOI: 10.1016/j.chembiol.2023.12.019

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of DNA damage. Yet, PARPi function mainly by trapping PARP1 onto DNA with a wide range of potency among the clinically relevant inhibitors. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon at sites of DNA damage that correlates with PARPi k_off. Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA-binding protein recruitment. These results clarify how PARPi trap, shed new light on how PARPi function, and describe how PARPi properties correlate to trapping potency.

Keywords: DNA damage repair; PARP; PARP inhibitor; PARP trapping; PARP1; dissociation rate; protein recruitment.