Incomplete paralog compensation and splicing regulation by TRA2A and TRA2B in cancer

Paralogous genes are widespread in the human genome and frequently retain overlapping functions, enabling cells to withstand the loss of one gene without compromising viability. In cancer, this functional redundancy provides resilience against genomic instability but also creates therapeutic opportunities through synthetic lethality, where co-disruption of both paralogs results in cell death. This dissertation explores the functional relationship between the splicing factor paralogs TRA2A and TRA2B, members of the serine/arginine-rich (SR) protein family. In a subset of cancer cell lines, TRA2A emerges as a selective dependency due to incomplete compensation by TRA2B, revealing a synthetic lethal interaction. TRA2A and TRA2B co-regulate a broad network of alternative and constitutive splicing events, particularly those involved in cell cycle and mitotic processes. While most cancer cells tolerate TRA2A loss, TRA2A-dependent lines exhibit insufficient TRA2B buffering, leading to widespread splicing dysregulation, mitotic defects, and apoptosis. To better understand the molecular basis of this redundancy, biochemical dissection reveals that the RNA recognition motifs and RS domains of TRA2A and TRA2B are functionally interchangeable. However, functionality is contingent on RNA engagement where loss of RNA binding capacity triggers proteasome-mediated degradation. These mechanistic insights help explain how subtle imbalances in TRA2 paralog function can compromise splicing fidelity and cell survival. Together, this work reveals how failure in paralog buffering can expose selective vulnerabilities in cancer and highlights the intricate coordination required between TRA2A and TRA2B to maintain proper splicing regulation.

Author dc:creator

• Lee, Amanda

Advisor dc:contributor.advisor

• Choi, Peter

• Biology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/61643

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/61643