# Structure and Mechanism of Chromatin-Bound PARP1

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $457,280

## Abstract

PROJECT SUMMARY
Poly(ADP-ribose) polymerase 1 (PARP1) is a promising target for cancer therapy in DNA repair-compromised
tumors. One PARP1 inhibitor (Olaparib) is used in the clinic to treat ovarian cancer, and ~20 phase III clinical
trials with inhibitors of PARP1 are currently ongoing. PARP1 is a highly abundant nuclear protein that upon
binding damaged DNA adds long chains of poly(ADP-ribose) onto itself and many other nuclear proteins. This
baroque post-translational modification recruits key components of the DNA repair machinery. Existing inhibitors
of PARP1 require a high effective dose (100-400 mg/day) and show poor correlation of drug efficacy with
inhibition of PARP1 activity, possibly because they also target inactive PARP1 that is abundantly bound to
undamaged chromatin. This PARP1 population has many nuclear functions that extend beyond the maintenance
of genome integrity, such as chromatin compaction, and the regulation of transcription and DNA methylation.
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. We aim to understand if selective
inhibition of the DNA-bound active conformation of PARP1 is a potential approach for increasing drug efficacy
and specificity. Using novel enzymatic assays, we will test the varied outcomes of activation by different types
of DNA damage. We also propose to investigate the interplay between PARP1 and the much less active and
less abundant PARP2. Our studies will reveal the conformational diversity of PARP1 and PARP2, and show how
this affects the complex reaction mechanism, resulting in different downstream signaling events. Our mechanistic
studies will provide key insights into how to design better screens and assays for the development of more
selective, mechanism-based PARP inhibitors. Altogether our proposed research will aid the development of the
next generation of PARP inhibitors for use in cancer therapy.

## Key facts

- **NIH application ID:** 9986447
- **Project number:** 5R01CA218255-04
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Karolin Luger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,280
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986447

## Citation

> US National Institutes of Health, RePORTER application 9986447, Structure and Mechanism of Chromatin-Bound PARP1 (5R01CA218255-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986447. Licensed CC0.

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