Elucidating molecular mechanisms of PARP2 at r loops in myelodysplastic syndromes
Active Project Grant Awarded Last action
- Award ID
- F31HL178160
- Recipient
-
Regents Of The University Of Minnesota UEI KABJZBBJ4B54
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $250,093
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 54% complete
- Place of performance
- Minneapolis, MN 55455, USA
Award details come from USAspending.gov.
Description
- Abstract
- Myelodysplastic syndromes (MDS), a group of blood disorders diagnosed in nearly 15,000 americans annually, are characterized by patients with high-risk MDS having a median survival of less than two years. Roughly half of all MDS patients possess a mutation in an RNA splicing factor (SF) gene: most commonly U2AF1, SRSF2, or SF3B1. Mutations in U2AF1 and SRSF2 are associated with faster disease progression to secondary acute myeloid leukemia and with poorer patient outcomes. Complicating treatment, MDS-associated SF mutations are mutually exclusive and cause unique patterns of alternative splicing events with non-overlapping outcomes, based on the individual mutations. Overcoming this, previous work in the nguyen lab identified r loops, three- stranded RNA:DNA hybrid transcription intermediates, as a unifying mechanism of disease pathogenesis induced by MDS-associated SF mutations. Recently, the lab further found that SF mutations sensitize cells to inhibitors of poly(ADP-ribose) polymerase (parp) enzymes, and that PARP1 plays a vital role in regulating r loops and maintaining genomic stability in SF-mutant cells. The proposed project aims to expand on this prior work by elucidating the mechanism by which PARP2 regulates r loops in cells possessing MDS-associated SF mutations. Preliminary results show that PARP2 associates with r loops, and that loss of PARP2 leads to both a reduction in ADP-ribosylation signaling in SF-mutant cells, and r-loop accumulation. In contrast, loss of PARP2 had no effect on ADP-ribosylation levels following direct DNA damage alone. PARP2 was also found to interact with the r-loop-resolving helicase DDX41. The central hypothesis of this project is that PARP2 plays a unique role at r loops to prevent r-loop-associated genomic instability in SF-mutant cells. This hypothesis will be tested through two specific aims evaluating PARP2 function at r loops: 1) elucidate how PARP2 senses r loops in U2AF1S34F cells, and 2) determine the impact of DDX41 ADP-ribosylation at r loops in SF-mutant cells. Results obtained through completion of these aims will provide new insights into how cells maintain genomic stability in response to r-loop accumulation, explicate a mechanism by which parp inhibitors sensitize SF-mutant cells, and potentially identify novel biomarkers to predict this sensitivity. This proposal will be completed at the university of minnesota, under the CO-mentorship of DR. HAI dang nguyen, an expert in the DNA damage response, r-loop regulation, and hematologic disorders, and DR. David largaespada (CO-sponsor), an expert in molecular-genetic mechanisms of pathogenesis. To complement this expertise, i will receive further guidance from my collaborators: DR. Stanley LEE, who specializes in mouse models of splicing-factor mutant MDS, and DR. Anthony leung, an expert in ADP-ribosylation signaling. This mentorship team, paired with the collaborative research environment, provides a unique opportunity for the candidate to complete the research aims described in this proposal and achieve his goal of becoming a molecular translational scientist working to uncover mechanisms of pathogenesis in hematologic disorders.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $35,887 | |
| Amendment | $35,887 | |
| Amendment | $564 | |
| Amendment | $564 | |
| Amendment | $35,323 | |
| Amendment | $35,323 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $35,323 | |
| Amendment | $0 | |
| Amendment | $35,323 | |
| Amendment | $35,323 | |
| Original award | $0 |
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Quick answers
Who received award F31HL178160?
F31HL178160 was awarded to Regents Of The University Of Minnesota by National Heart Lung and Blood Institute (National Institutes of Health) on June 1, 2025.
How much is award F31HL178160 worth?
$250,093 has been obligated on F31HL178160.
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