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Regulation of Acute Myeloid Leukemia Cell Proliferation by E3 Ubiquitin Ligase DCAF15 Control of Cohesin Dynamics / Grant Peter Grothusen.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Grothusen, Grant Peter, author.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Cellular biology.
- Genetics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Molecular biology.
- Cellular biology.
- Genetics.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (147 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell-autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Busino, Luca; Committee members: Carroll, Martin P.; Hua, Xianxin; Asangani, Irfan A.; Shi, Junwei.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381510102
- Access Restriction:
- Restricted for use by site license.
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