Oncogene Induced Senescence Alters Genomic Susceptibility to UV-Induced DNA Lesions
Abstract/Contents
- Abstract
- Oncogene Induced Senescence (OIS) is a tumor suppressive pathway that halts cell cycle progression in response to oncogene activation. During the development of cutaneous melanomas, mutational escape from OIS is a key contributor to the onset of overt malignancy. However, the origins of the escape process itself remain poorly understood. It is unclear if escape mutations arise solely through the random acquisition of DNA lesions, or if lesion acquisition is predetermined by the extensive epigenetic changes associated with OIS entry. To address this knowledge gap, we applied TRansposase Assisted Damage Sequencing (TRAD-Seq) to characterize changes in genomic susceptibility to UV-induced Cyclobutane Pyrimidine Dimers (CPDs) in a melanoma OIS model. We found a global increase in CPD susceptibility that is particularly pronounced in Differentially Susceptible Regions (DSRs) characterized by depletion of lamin B1 and enrichment of H3K9me3. Top-ranked DSRs encompass a range of cancer-associated genes relevant to melanoma development, including the CDKN2A/p16 locus implicated in OIS-escape. Furthermore, DSRs overlap with structural mutation hotspots identified in an Australian melanoma sequencing cohort, suggesting that differential CPD susceptibility underlies large-scale genomic instabilities seen in clinical melanomas. Together, our results show that OIS-driven epigenomic reorganization alters CPD susceptibility in a manner conductive to melanoma development and senescence escape.
Description
| Type of resource | text |
|---|---|
| Date created | June 2021 |
| Date modified | December 5, 2022 |
| Publication date | April 25, 2022 |
Creators/Contributors
| Author | Liu, Eric |
|---|---|
| Research team head | Morrison, Ashby |
| Thesis advisor | Montgomery, Stephen |
Subjects
| Subject | Department of Biology |
|---|---|
| Subject | Melanoma |
| Subject | Epigenetics |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
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- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
Preferred citation
- Preferred citation
- Liu, Eric and Morrison, Ashby and Montgomery, Stephen. (2021). Oncogene Induced Senescence Alters Genomic Susceptibility to UV-Induced DNA Lesions. Stanford Digital Repository. Available at: https://purl.stanford.edu/hk237by4260
Collection
Undergraduate Theses, Department of Biology, 2020-2021
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- eliu31@stanford.edu
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