Investigating novel mechanisms of Translesion Synthesis (TLS) regulation in cancer

Public Deposited

Analytics

Last Modified

Creator

Holk, Alicia
- Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology

Abstract

Cells are subjected to a range of DNA damaging agents from intrinsic, environmental, and therapeutic sources. The ability to cope with DNA damage is essential for maintaining genomic stability and preventing disease. Trans-lesion Synthesis(TLS) is a mechanism by which cells tolerate DNA damage by utilizing flexible, albeit error-prone, polymerases to bypass DNA lesions. Here we show that aberrantly expressed cancer testes antigen, Melanoma-Associated Antigen 4 (MAGE-A4), is a unique regulator of TLS in many neoplastic cells, demonstrating a novel mechanism for both mutagenesis and therapy-resistant cancer. Owing to its role in chemoresistance, TLS represents an appealing pathway for targeted cancer therapies. As an initial step in the drug discovery process we have identified small molecule inhibitors which target the essential interaction between TLS Polymerase Eta and mono-ubiquitinated PCNA. Taken together, we have identified a new mechanism for conferring tumorigenic phenotypes and initiated efforts to target this pathway for therapeutic purposes.

Date of publication

Keyword

DOI

Resource type

Rights statement

Advisor

Degree

Degree granting institution

Graduation year

Language

Relations

There are no publicly available items in this Dissertation or Thesis.