The RAD18 E3 Ubiquitin Ligase: A Novel Target for Cancer Therapy

 

Trainee:

Alicia Greenwalt

DeSimone

Research Mentor:

Dr. Cyrus Vaziri

unavailable

Clinical Co-Mentor;

Dr. Kimryn

Rathmell, MD, PhD

Rathmel
Department: Genetics
Project Description:

Platinating agents, such as cis-platinum (CDDP), are among the most widely used therapies for ovarian, testicular and other cancers. Acquired resistance to platinating agents is a major limitation of existing chemotherapies. Common mechanisms of resistance, (which may not be mutually exclusive), include decreased drug uptake, increased drug metabolism and increased DNA damage tolerance. A major mechanism of DNA damage tolerance results from a pathway known as Trans-lesion Synthesis (TLS). When DNA polymerases stall at bulky adducts a ‘polymerase switch’ recruits alternative, TLS polymerases, which can accommodate bulky DNA lesions such as CDDP and allow completion of DNA replication, albeit at an increased risk of mutagenesis.

A TLS polymerase termed DNA polymerase eta (PolH) is able to bypass CDDP adducts and provides a potential mechanism for platinum-resistance in cancer cells. The recruitment of PolH to stalled replication forks is dependent on an E3 Ubiquitin ligase known as RAD18. RAD18 is responsible for monoubiquitinating the DNA replication protein, PCNA. Upon monoubiquitination, PCNA binds PolH and initiates TLS. Due to the key role of TLS in tolerance of CDDP-induced DNA damage, we propose to investigate RAD18 and PolH as novel drug targets for combination therapy with platinating agents.