# The catalytic and non-catalytic functions of PARP1 in cancer biology

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $366,000

## Abstract

Cancer radiation therapy generates DNA lesions and reactive oxygen species, which activate Poly
ADP-ribose polymerase 1 (PARP1) and its related family member PARP2. Activated PARP1/2 transfers ADP-
Ribose to themselves and histones. The resulted poly (ADP-ribose) (PAR) chains further recruit others repair
proteins (e.g. XRCC1-Lig3 complex). Specific inhibitors for both PARP1 and 2 (refer to as PARPi) preferentially
target BRCA1/2 deficient cancer cells and synergize with other genotoxic cancer therapies, including radiation.
While these effects were originally attributed to the lack of PAR dependent recruitment of XRCC1, deletion of
XRCC1 does not have the same cytotoxicity as PARPi. More recently PARPi was found to trap PARP1 at DNA
breaks, converting transient PARP1 foci (<10min) to durable ones (>30 min). If not removed, the PARP1-DNA
adduct can prevent DNA repair and stall replication. Accordingly PARP1 deletion “desensitizes” cancer cells to
PARPi, revealing a structural function of PARP1 in cancer therapy. In preliminary studies, we found
unexpectedly the release of PARP1 from DNA is regulated by PARP2 and mono-ADP-ribosylation
(MARylation), but not PARylation. To understand this structural function of PARP1 in vivo, we generated
mouse models expressing constitutive (Parp1A) or inducible (Parp1AN) PARylation defective PARP1 (E988A)
and a conditional PARP1 mouse model (Parp1C). In contrast to the normal development and gender
distribution of Parp1-/- mice, Parp1+/A mice display female specific embryonic lethality. And male Parp1+/A cells
display severe hypersensitivity to DNA damage agents beyond what is found in Parp1-/- ctrl. Given the
application of PARP inhibitor in cancer types almost exclusively affecting women (breast and ovarian), this
gender bias is intriguing and might be caused by the breaks independent binding of PARP1 on the chromatin
and an role of PARP1 protein in X-inactivation and other epigenetic regulation. Female Parp1+/-Parp2-/- (but not
Parp1-/-Parp2+/-) mice also display female specific lethality accompanied by X-chromosome specific instability.
Based on these findings, we hypothesize that PARP1 has structural function in chromatin biology and DNA
repair that are critical for cancer therapy. To test this, we will use mouse genetics, structural biology and cell
biology approaches to 1) determine the mechanism that regulates PARP1 dynamics at DNA damage sites,
reveal the biological consequence of PARP1 trapping and 2) characterize PARP1 E988A mouse models to
determine the impact of catalytic inactive PARP1 on DNA repair, X-inactivation, oncogenesis in vivo. The
completion of this study will elucidate the previously un-recognized structural function of PARP1, reveal
functional interactions between PARP1 and PARP2 and the gender specific role of PARP1 in female. In the
near future, the mechanism and the novel animal models generated in the course of our study will also
facilitate the development and use of PARP inhibitors ...

## Key facts

- **NIH application ID:** 10120643
- **Project number:** 5R01CA226852-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shan Zha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120643

## Citation

> US National Institutes of Health, RePORTER application 10120643, The catalytic and non-catalytic functions of PARP1 in cancer biology (5R01CA226852-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120643. Licensed CC0.

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