Mechanisms of DNA damage processing and the initiation of nucleotide excision repair
Ended Project Grant Awarded Last action
- Award ID
- R15GM147899
- Recipient
-
Baylor University UEI C6T9BYG5EYX5
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $754,986
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date
- Originally
- Place of performance
- Waco, TX 76798, USA
Award details come from USAspending.gov.
Description
- Abstract
- Mechanisms of DNA damage processing and the initiation of nucleotide excision repair the goal of this research is to determine the structural mechanism of nucleotide excision repair (NER) initiation. NER is the most versatile DNA repair mechanism that repairs a wide variety of DNA lesions through a multistep process involving over 30 different proteins. Being essential to maintaining genome integrity, this pathway is also highly conserved from yeast to humans. Genetic defects in NER factors lead to phenotypes ranging from extreme cancer predisposition syndrome (xeroderma pigmentosum) to severe neurodevelopmental defects (cockayne syndrome), thus providing a unique paradigm to understand diverse clinical outcomes of DNA damage. Recent studies also revealed NER as a major contributor of somatic mutation hotspots in various sporadic cancers and NER has been suggested as an attractive target for anti-cancer therapy. Despite its biological and medical importance, delineating the mechanisms of NER has been a long-term challenge due to the complex compositions and functions of NER factors and the lack of comprehensive structural understanding of their interplay on DNA. This proposal aims to define the mechanism of NER initiation in detailed 3D structures using cryo-EM combined with time- resolved fluorescence spectroscopy and crosslinking/mass-spectrometry. The outcome will answer fundamental questions regarding (1) how the two key NER initiators, RAD4-RAD23-RAD33 (yeast homolog of XPC-RAD23B-CETN2) and tfiih, together start the DNA 'opening' around the damage - a critical step in NER initiation, and (2) how the torsional stress in DNA impacts this process. This understanding will provide the foundation to explain various pathophysiologies involving NER, which in turn can lead to novel strategies to counter various NER-linked diseases including cancer. Importantly, our research will provide solid training grounds for several undergraduate researchers every year and will significantly enhance the biomedical research environment at baylor university, an undergraduate-focused institution, through its intimate collaboration with upenn medical school. Immersed in an interdisciplinary research project with access to cutting- edge technologies, our undergraduate researchers will gain expertise in various biochemical and biophysical approaches and grow as key drivers of significant science.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $377,493 | |
| Original award | $377,493 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| The Trustees Of The University Of Pennsylvania | $131,267 |
Quick answers
Who received award R15GM147899?
R15GM147899 was awarded to Baylor University by National Institute of General Medical Sciences (National Institutes of Health) on September 1, 2022.
How much is award R15GM147899 worth?
$754,986 has been obligated on R15GM147899.
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