Dissecting the role of the fanconi anemia pathway in chromothripsis
Ended Project Grant Awarded Last action
- Award ID
- F31CA295091
- Recipient
-
The University Of Texas Southwestern Medical Center UEI YZJ6DKPM4W63 Part of University Of Texas System
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $132,655
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date
- Place of performance
- Dallas, TX 75390, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cancer-associated chromosomal abnormalities frequently arise through punctuated episodes of genomic instability. This is exemplified by chromothripsis, the shattering and RE-stitching of individual chromosomes, which generates a distinct rearrangement signature in ~30% of pan-cancer genomes. Chromothripsis is driven by mitotic errors and the formation of aberrant nuclear bodies termed micronuclei that entrap MIS-segregated chromosomes outside of the nucleus. Due to defects in nuclear envelope assembly, micronuclei undergo frequent and irreversible rupture that inactivates normal nuclear processes, including DNA replication, DNA repair, and transcription. During mitotic entry, chromosomes in micronuclei undergo extensive breakage into tens to hundreds of fragments through incompletely defined mechanism(s). Our laboratory recently identified that fragmented chromosomes remain bound throughout mitosis by protein-mediated tethers, which facilitates the RE-incorporation of the fragments into the nucleus and its subsequent reassembly. This cascade gives rise to the highly complex yet localized rearrangements that are often observed in cancer genomes. In addition to the deletion of tumor suppressor genes and/or formation of oncogenic fusion genes, chromothripsis can also result in the circularization and amplification of genes on extrachromosomal dnas (ecdnas). While several key mechanistic steps have been well characterized, the source(s) of mitotic chromosome fragmentation remain unclear. To identify genetic drivers of chromothripsis, i recently conducted pooled crispr-CAS9 screens using a chromosome-specific micronucleus system. I unexpectedly identified that a genome maintenance mechanism known as the fanconi anemia (FA) pathway functions as a critical driver of chromothripsis and complex genomic rearrangements. My preliminary data suggest that the FA pathway promotes mitotic chromosome shattering through the recruitment of structure-specific DNA endonucleases to under-replicated DNA intermediates from micronuclei, which is then followed by mitotic DNA synthesis, a process that may be analogous to the processing of late-replicating fragile sites in the genome. Here i propose to further define the role of the FA pathway and mitotic DNA synthesis in chromothripsis. First, i will comprehensively identify regions of the micronucleated chromosome undergoing active processing during mitosis by the FA pathway. I will also determine whether mitotic DNA synthesis is required for priming fragments for reassembly in the next cell cycle. Second, i will leverage pre-clinical cell models to investigate whether inhibition of the FA pathway represents a feasible therapeutic strategy to suppress chromothripsis-induced emergence of drug-resistant cancer cells harboring ecdnas. These studies will shed light on how a genome-protective DNA repair mechanism can be CO-opted as a pathological driver of cancer genome instability. In addition to this research plan and with support from my sponsor, CO-sponsor, and dissertation committee, i have also established a well-defined training and career development plan that will further bolster my abilities as an independent researcher focused on cancer biology.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$12,840 | |
| Amendment | -$107 | |
| Amendment | -$27,510 | |
| Amendment | -$27,510 | |
| Amendment | $40,350 | |
| Amendment | $40,350 | |
| Amendment | $40,350 | |
| Amendment | $39,786 | |
| Amendment | $39,786 | |
| Original award | $0 |
Quick answers
Who received award F31CA295091?
F31CA295091 was awarded to The University Of Texas Southwestern Medical Center by National Cancer Institute (National Institutes of Health) on December 1, 2024.
How much is award F31CA295091 worth?
$132,655 has been obligated on F31CA295091.
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