# The non-catalytic function of PARP2 in DNA repair and cancer therapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $565,118

## Abstract

PROJECT SUMMARY/ABSTRACT
 PARP1 and PARP2 are DNA damage-induced poly-ADP-ribose (PAR) transferases, which are recruited
to and activated by DNA breaks. Active PARP1&2 PARylate themselves and histones to promote DNA repair
and chromatin relaxation. Dual-specificity inhibitors (PARPi) for PARP1 and PARP2 are currently used for the
treatment of BRCA1/2-deficient breast, ovarian, pancreatic, and prostate cancers. However, severe anemia
occurs in ~ one-third of patients, leading to dose reduction and premature termination of PAPRi therapy. PARPi
also cause significant clonal hematopoiesis, a condition that increases the risk for myeloid dysplasia and acute-
myeloid leukemia (MDS/AML). These hematopoietic toxicities are unexpected since the complete loss of Parp1
that is responsible for >80% of DNA damage-induced PARylation in cells, has no impact on hematopoiesis. To
understand this potential on-target toxicity of PARPi, we generated mouse models with knockin catalytically
inactive mutations in Parp2 – Poly-ADP-Ribosylation (PARylation) deficient (E534A, Parp2EA) or Mono-ADP-
Ribosylation (MARylation) deficient (H404A, Parp2HA). In contrast to the normal development of Parp2-/- mice,
mice expressing PARylation deficient PARP2 (Parp2EA/EA) died at embryonic day 16.5 (E16.5) with severe
anemia and stage-specific blocks in erythropoiesis. The Parp2HA/HA mice are viable but display splenomegaly
and chronic anemia. Meanwhile, our cell biology analyses suggest that clinically used PARPi effectively stalls
PARP2, but not PARP1, on laser-induced DNA damage sites. Based on these and other observations, we
hypothesize that PARP2 has PARylation-dependent structural functions that preferentially block nick
ligation during DNA replication, underlie the PARP inhibitors-induced erythropoiesis defects and anemia.
Specifically, we propose that catalytically inactive PARP2 were trapped on DNA breaks, especially 5’pho-nicks,
where they prevent other repair factors (e.g., Ligase1) from accessing the DNA nicks. Correspondingly, like the
Parp2EA/EA mice, Lig1-/- mice also succumbed to lethal anemia at E16.5. To test our hypothesis, we will Aim 1)
investigate the mechanism that regulates PARP2 recruitment and dynamics at DNA damage sites using live-cell
imaging and bulk biochemical assays; Aim 2) determine the impacts of catalytically inactive PARP2 on the
recruitment and function of other DNA repair factors, and DNA replication in vivo and in vitro; Aim 3) characterize
the mouse models expressing catalytically inactive - Parp2 and investigate how the loss of Trp53, CHK2, two
genes associated clonal hematopoiesis, modulates the anemia in Parp2EA/EA models. The completion of the
proposal will characterize the previously unrecognized structural functions of PARP2, address how catalytically
inactive PARP2 compromises DNA replication and selectively abrogates erythropoiesis, providing the strategy
to mitigate this on-targeted toxicity of PARP inhibitors by reducing PARP2 stall...

## Key facts

- **NIH application ID:** 10850707
- **Project number:** 5R01CA271595-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shan Zha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,118
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10850707

## Citation

> US National Institutes of Health, RePORTER application 10850707, The non-catalytic function of PARP2 in DNA repair and cancer therapy (5R01CA271595-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10850707. Licensed CC0.

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