# Structure and Mechanism of Chromatin-Bound PARP1

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2024 · $43,811

## Abstract

PROJECT SUMMARY
Inhibitors of the nuclear enzyme PARP1 (PARPi) are in clinical use and advanced trials as therapeutics for
cancers with DNA damage repair defects. PARP1 is a highly abundant protein that shapes chromatin structure,
but upon detecting damaged DNA becomes enzymatically active and builds chains of poly(ADP)-ribose (PAR)
on itself. PARylation of other nuclear proteins such as histones is mediated by the recently discovered Histone
PARylation Factor 1 (HPF1). PARylation relaxes compact chromatin and serves as a signal to recruit the DNA
repair machinery, but access of the DNA damage repair machinery also relies on the action of ATP-dependent
chromatin remodeling factors and histone chaperones. The efficacy of PARP inhibitors in cancer patients is
attributed to synthetic lethality: Simultaneously shutting down PARP-mediated DNA repair in patients with
deficiencies in DNA repair pathways (i.e. BRCA1/2 negative) or with induced DNA damage (i.e. chemo- or
radiotherapy), leads to overwhelming DNA damage and cancer cell death. Despite the success of existing
inhibitors of PARP1, high effective dosages, poor correlation of drug efficacy with inhibition of PARP1 activity in
cancer cells, and resistance to PARPi suggest room for improvement.
Our goal is to use rigorous quantitative, structural, and mechanistic approaches to investigate how PARP1
interacts differently with damaged vs. intact DNA in the context of chromatin, and in the presence or absence of
its accessory protein HPF1. We aim to discover whether next-generation PARPi should be optimized for binding
more tightly to the PARP1-HPF1 complex, or instead prevent this complex from forming, and whether these
properties should differ for different clinical applications (i.e. cancer vs. cardiovascular or neurological diseases).
We also seek to investigate whether selective inhibition of the DNA-bound active conformation of PARP1 is a
potential approach to lowering the amount of drug one would need to administer, by illuminating the
conformational diversity of PARP1 bound to intact vs. damaged chromatin through structural biology. Finally, we
will determine the effect of PARylation on the ability of chromatin remodelers to provide better access to the DNA
repair machinery. Our mechanistic studies will yield key insights into how to design better screens or assays for
the development of more selective and mechanism-based PARP inhibitors. Altogether our proposed research
will inform the development of the next generation of PARP inhibitors for use in cancer therapy.

## Key facts

- **NIH application ID:** 10892149
- **Project number:** 5R01CA218255-08
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Karolin Luger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,811
- **Award type:** 5
- **Project period:** 2017-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892149

## Citation

> US National Institutes of Health, RePORTER application 10892149, Structure and Mechanism of Chromatin-Bound PARP1 (5R01CA218255-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10892149. Licensed CC0.

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