# Regulation and function of site-specific protein poly-ADP-ribosylation

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $410,000

## Abstract

PROJECT SUMMARY
Protein ADP-ribosylation (ADPr) is a dynamic, NAD+-dependent post-translational modification. The mammalian
poly(ADP-ribose) polymerase (PARP) proteins that catalyze ADPr target several chemically distinct amino acid
side chain functionalities on hundreds of substrate proteins to mediate a multitude of orthogonal signal
transduction pathways. Adding to this complexity is the potential for ADP-ribose polymer formation, a process
wherein the PARP1/2 and TNKS1/2 enzymes elongate ADP-ribose chains from mono-ADPr sites. Highlighting
the importance of poly-ADP-ribose in physiology and disease are: (i) the expanding clinical utility of PARP1/2
inhibitors to treat DNA repair-deficient cancers, and (ii) TNKS1/2 function in Wnt/b-catenin signaling and
dysfunction in developmental diseases including Cherubism. Aberrant ADPr activity has also been reported as
an underlying cause of cardiovascular and neurogenerative diseases, and these findings have inspired intense
efforts to elucidate PARP substrate profiles, determine PARP regulatory mechanisms, and develop PARP
isoform-specific inhibitors. However, given the liberal deployment of ADPr in cellular signaling and its
topologically complex chemical nature, our understanding of how specific mono- and poly-ADPr sites impact
protein function and elicit distinct biological activities has lagged behind. The proposed work aims to fill this
knowledge gap by developing novel approaches to reconstitute ADPr-mediated signaling events in highly
controlled biochemical and cellular environments. We recently developed a chemoenzymatic strategy to install
serine ADPr onto peptides and proteins with full control over modification site and ADP-ribose chain length.
Using this technology, we identified critical molecular determinants of DNA damage-induced chromatin
remodeling and uncovered specialized functions for nucleosome serine poly-ADPr. We are now in a unique
position to build upon our technologies and address fundamental questions in PARP biology. We will explore
mechanisms that govern poly-ADPr activity and investigate how different modification sites and accompanying
polymer lengths encode for specific biochemical outputs throughout the cell. Such information may guide more
effective strategies to identify and treat diseases that rely on dysfunctional ADPr activity.

## Key facts

- **NIH application ID:** 10498680
- **Project number:** 1R35GM147140-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Glen Liszczak
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498680

## Citation

> US National Institutes of Health, RePORTER application 10498680, Regulation and function of site-specific protein poly-ADP-ribosylation (1R35GM147140-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10498680. Licensed CC0.

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