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SoCoBio (Universities of Southampton, Kent, Sussex, Portsmouth and NIAB EMR)

How does mis-activation of testis-specific genes disrupt mitotic cell division? (CASE project)

Primary Supervisor: Peter Ellis (University of Kent)
Secondary Supervisor : Tim Fenton (University of Kent)
Industry CASE partner: Lee Larcombe (Applied Exomics)

Project Summary:

Background and rationale
Developing germ cells within the testis show a suite of unusual characteristics, including high proliferation rates in pre-meiotic spermatogonia, genome-wide genetic rearrangement and tolerance to DNA damage in spermatocytes, and extensive cellular remodelling and metabolic rewiring in post-meiotic spermatids. These aspects of germ cell biology must be tightly regulated in order to keep cell division in check and prevent harmful over-proliferation. Preliminary research in our laboratory suggests that in some cases, virus infection may induce a limited soma/germline transition that alters cell division checkpoints and facilitates survival. In other words, these viruses hijack elements of the meiotic programme to drive their own proliferation. This in turn may lead to cancer formation since the normal safeguards on cell division have been bypassed.

Experimental approach
Using both normal cells and head and neck squamous cell carcinoma (HNSCC) cells as a model, this project will study how meiosis-specific genes interact with human papilloma virus (HPV) infection to drive cell proliferation. Specifically, we will investigate (1) whether HPV-driven overexpression of the essential meiotic gene SYCP2 leads to genome instability by altering DNA recombination in infected cells, and (2) whether mis-expression of the Y-linked meiotic genes RBMY and ZFY provides a biological basis for the higher rates of HPV infection and HNSCC in men relative to women.

Areas of Impact
This project represents an interdisciplinary collaboration between reproductive medicine, cancer and bioinformatics groups. While the principal outcomes here are a better understanding of the basic science of how meiotic genes act when wrongfully expressed in non-meiotic cell types, there are also potential downstream applications in both diagnosis and treatment of malignancies.