Mechanisms of epigenetic disruption due to DNA damage and replication stress
Active Project Grant Awarded Last action
- Award ID
- F31CA310572
- Recipient
-
President And Fellows Of Harvard College UEI JDLVAVGYJQ21 Part of Harvard College President & Fellows Of
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $72,916
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- Boston, MA 02115, USA
Award details come from USAspending.gov.
Description
- Abstract
- Epigenetic memory of gene expression programs is critical for the development and maintenance of cellular identity. Epigenetic dysregulation is a hallmark of human cancers, as widespread alterations in gene expression can lead to misexpression of oncogenes or inappropriate repression of tumor suppressor genes. Different cell types have different epigenetic signatures which may require different epigenetic targets as cancer therapies. Additionally, treatment resistance is a common problem in current cancer therapies. Understanding how epigenetic fidelity is initially lost may provide critical insights for the future development of cancer therapies. Prior work has shown that DNA damage causes widespread epigenetic dysregulation. Additionally, there is strong evidence that replication stress disrupts the inheritance of heterochromatin, which then leads to derepression of cell type-specific genes and loss of cell identity. The precise mechanisms of this epigenetic loss are unknown. Cells face genomic threats such as endogenous DNA damage and replication fork stalling in each cell division. IT is important to understand how these challenges contribute to epigenetic disruptions. In the proposed work, I seek to define how two threats to epigenetic stability, DNA repair of double stranded breaks and replication stress, affect heterochromatin maintenance. Using fission yeast, a powerful model for heterochromatin inheritance, I will seek to identify the steps in DNA repair and fork stalling which lead to heterochromatin loss. In aim 1, I propose to induce double strand breaks at a targeted, inducible heterochromatin locus using crispr- CAS9 to first define the effects of double strand breaks on heterochromatin maintenance and second, determine whether distinct repair pathways differentially affect heterochromatin maintenance. In aim 2, I propose to determine how sequences predicted to stall the replisome affect heterochromatin maintenance. In aim 3, I will seek to identify novel pathways which have roles in maintaining epigenetic fidelity in the face of replication stress and DNA repair by performing a genetic screen.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $36,458 | |
| Amendment | $36,458 | |
| Original award | $0 |
Quick answers
Who received award F31CA310572?
F31CA310572 was awarded to President And Fellows Of Harvard College by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F31CA310572 worth?
$72,916 has been obligated on F31CA310572.
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