# Implications of PARP1 in myelodysplastic syndromes and targeted therapy

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $503,056

## Abstract

PROJECT SUMMARY/ABSTRACT
Myelodysplastic syndromes (MDS), a heterogenous group of clonal hematopoietic stem cell disorders, are an
acquired bone marrow failure syndrome. MDS is characterized by ineffective hematopoiesis resulting in
peripheral blood cytopenia and progenitor expansion. Genes encoding for RNA splicing factors (U2AF1, SF3B1,
SRSF2, and ZRSR2) are frequently mutated and occur in the founding clones of MDS, representing a unique
class of genetic vulnerability for targeted therapy. However, despite the prevalence of spliceosome mutations,
how such mutations impact different cellular mechanisms are largely unclear. Recent studies by us and others
suggest that R-loops, a group of transcription intermediates containing RNA:DNA hybrids and displaced single-
stranded DNA, are a source of genomic instability induced by different spliceosome mutants. In the preliminary
studies leading to this application, we find that PARP1 is activated by R-loops and it plays a key role in
suppressing R-loop-associated DNA damage. Furthermore, we show that MDS-associated RNA splicing factor
mutations promote R-loop accumulation and render cells sensitive to PARP inhibition. These exciting findings
lead us to hypothesize that PARP1 is a key sensor of R-loops and a critical suppressor of R-loop-associated
DNA damage. Furthermore, aberrant R-loop accumulation represents a new targetable vulnerability in MDS-
associated splicing factor mutant cells, making PARP inhibition an attractive way to target R-loop vulnerability in
MDS. Finally, since PARP inhibitors achieved limited FDA approval in different diseases, repurposing PARP
inhibitors to treat MDS patients harboring RNA splicing factor mutations may provide the fastest route to translate
our findings to the clinics. To test these hypotheses, in Aim 1, we will elucidate mechanisms by which PARP1 is
activated by R-loops. In Aim 2, we will identify global PARP1 substrates and R-loop distribution landscape in
U2AF1-mutant cells, providing a proteomic and genomic view of how PARP1 regulates R-loops. In Aim 3, we
will evaluate whether PARP inhibitor, olaparib, can selectively eliminate MDS-associated splicing mutant cells in
vitro and in vivo. Together, these studies will mechanistically explain how R-loops are sensed by PARP1 in
splicing mutant cells, reveal how PARP1 guards cells against R-loop-associated genomic instability, and address
whether R-loop-associated vulnerability in spliceosome-mutant MDS cells can be exploited by PARP inhibitors
as targeted MDS therapy. The combined expertise in R-loops, PARP1, DNA damage response and spliceosome
mutations in MDS (Nguyen laboratory), PARP regulation by proteomic approach (Leung laboratory, co-I), and
MDS GEMM mouse models of U2AF1 and SRSF2 mutations (Lee laboratory, co-I) provides us the unique
opportunity to characterize PARP1 function in cells expressing MDS-associated mutations. These studies will
not only significantly advance our understanding of R-loop biolo...

## Key facts

- **NIH application ID:** 10834091
- **Project number:** 5R01HL163011-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Dang Hai Nguyen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,056
- **Award type:** 5
- **Project period:** 2022-05-20 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834091

## Citation

> US National Institutes of Health, RePORTER application 10834091, Implications of PARP1 in myelodysplastic syndromes and targeted therapy (5R01HL163011-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834091. Licensed CC0.

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