The centromeric roles of synaptonemal complex proteins in meiosis and cancer

Meiotic cell division involves an extraordinary choreography in which homologous chromosomes exchange genetic material and are then segregated to form haploid germ cells. The molecular machines that perform these essential functions also contribute to a latent toolbox of chromosome remodelling and recombination factors that are frequently expressed aberrantly in cancer.

As their only biological roles are in meiosis, these meiotic cancer-associated factors are attractive for providing selective toxicity in novel cancer therapies.

The synaptonemal complex (SC) is a is a supramolecular protein structure that binds homologous chromosomes together in synapsis, facilitating recombination and crossover formation, and is essential for fertility. SC proteins also have a poorly defined role in the centromere, as observed during natural meiosis, and upon expression in mitotic cells. Further, SC proteins are frequently expressed in human cancers, where cancer development and prognosis are closely linked to SC protein expression.

The pathological roles of SC proteins in cancer have been associated with their localisation to the centromere and other microtubule-associated structures. However, it remains unknown how SC proteins are recruited to the centromere, its function in meiosis and how it contributes to cancer.

This PhD project aims to how mammalian SC proteins are recruited to the centromere, its biological role in meiosis, and its pathological role in the development of human cancers. We will focus on SC proteins SYCP1, SYCP2 and TEX12, which have a number of verified direct interactions with centromere proteins, and are clearly associated with the development of cancer.

We will determine the structure of SC-centromere complexes by X-ray crystallography and Cryo-EM, alongside solution biophysics (MALS and SAXS). Centromere associations will tested through separation-of-function mutagenesis in somatic cell culture systems, and in cancer development through collaborative mouse genetics.