A pseudo-meiotic centrosomal function of TEX12 in cancer

Abstract

Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes. The many meiosis-specific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer. Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis, is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis. We find that TEX12 knock-down causes proliferative failure in multiple cancer cell lines, and confirm its role in the early stages of oncogenesis through murine cancer models. Remarkably, somatically expressed TEX12 localises to centrosomes, leading to altered centrosome number and structure, features associated with cancer development. Further, we identify TEX12 in meiotic centrin-rich bodies, likely precursors of the mitotic centrosome, suggesting that this may represent an additional cellular function of TEX12 in meiosis that has been previously overlooked. Thus, we propose that an otherwise meiotic function of TEX12 in centrosome duplication is responsible for promoting oncogenesis and cellular proliferation in cancer, which may be targeted for novel cancer therapeutics and diagnostics.

Structural basis of meiotic chromosome synaptic elongation through hierarchical fibrous assembly of SYCE2-TEX12

“…It successfully predicted several important aspects of SYCE2-TEX12 structure, such as the parallel arrangement of elongated SYCE2 chains and a dominant interaction between SYCE2 N-termini and TEX12 C-termini within the 4:4 complex (Davies et al, 2012). However, a notable difference is that our previous model was built on the assumption of constituent TEX12 dimers, owing to their behaviour as such in solution, which we now know represents an entirely distinct structural and functional form of TEX12 (Sandhu et al, 2019). This led to the incorrect placement of TEX12 dimers flanking an SYCE2 core rather than intertwined within the hetero-octamer, and the prediction that the over-estimated 40-nm length of a heteroctamer could account for the width of the SYCE2-TEX12 fibres.…”

Meiosis initiation: a story of two sexes in all creatures great and small

“…To address this issue, the term Germ Cell Cancer Genes (GCCG) has been proposed to describe the variety of meiotic genes re-expressed in cancer cells [121]. Currently over a thousand GCCGs have been reported widely re-expressed across cancer types, highlighting the importance of this process (see below) [105,[121][122][123][124].…”

“…The presence of meiotic proteins in cells other than germ also brings into to question the validity of the Weismann barrier hypothesis [ 121 , 122 , 125 ], which now needs to be evaluated experimentally through a combination of cell signalling, epigenetic and transcriptional analyses. Indeed, it is now timely to consider whether genes required for meiosis specific processes might also possess non-meiotic functions; such ‘moonlighting’ functions have been characterised for a number of human mitotic proteins including the HSP family members, clathrin and dynein [ 126 ].…”

“…Indeed, it is now timely to consider whether genes required for meiosis specific processes might also possess non-meiotic functions; such ‘moonlighting’ functions have been characterised for a number of human mitotic proteins including the HSP family members, clathrin and dynein [ 126 ]. Recently, we identified a novel, ‘moonlighting’ function for the meiotic protein TEX12 (Testis Expressed 12) within microtubule organising centres, organelles that are fundamental for meiosis and mitosis [ 122 ]. TEX12 gene transcription and protein expression were originally believed to be exclusively meiotic with expressed protein restricted to the meiosis-specific synaptonemal complex, which assembles between aligned homologous chromosomes during prophase to facilitate DNA recombination.…”

“…Similar moonlighting functions have been previously reported for other meiotic proteins such as Sme4 and Hei10 [ 127 , 128 ]. Furthermore, we found TEX12 to be a GCCG that is widely expressed in ∼15% of cancer patients [ 122 ]. Frequent expression of TEX12, and other meiotic genes in human cancers highlights that the process of oncogenesis might recreate, or be triggered by, some of the conditions characteristic of meiotic initiation resulting in large scale activation of the meiotic transcriptome.…”