Head of fruit fly in cross section

James Turner group project:

The molecular genetics of MSCI / MSUC

During male meiotic prophase the sex chromosomes become transcriptionally silenced (Meiotic Sex Chromosome Inactivation; MSCI) and are sequestered in a specialised chromatin domain termed the XY- or sex-body. We have established that MSCI is dependent on serine-139 phosphorylation of the histone variant H2AX (γH2AX). Several indirect lines of evidence suggest that phosphorylation of H2AX is carried out by the Seckel syndrome kinase ATR, and that localisation of ATR to the sex chromosomes is in turn dependent upon the tumour suppressor BRCA1.

Silencing of the X and Y during male meiosis is a consequence of the fact that they are unsynapsed during normal male meiosis. When an additional synaptic sex chromosome partner is provided for either the X or Y during meiosis, the sex chromosome escapes silencing. Furthermore, unsynapsed autosomes are also subject to silencing during both male and female meiosis. We call this general silencing phenomenon Meiotic Silencing of Unsynapsed Chromatin (MSUC). MSUC is mediated in the same way as MSCI, i.e. using BRCA1, ATR and H2AX.

Figure 1

Figure 1

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A molecular model for MSCI. Shortly before MSCI, BRCA1 coats the unsynapsed regions of the X and Y chromosome (arrows). This is followed by BRCA1-dependent recruitment of ATR, and finally phosphorlyation of H2AX to form γH2AX. Silencing occurs as soon as phosphorylation is initiated.

We are currently testing the role of ATR in MSCI / MSUC directly using two different strategies by which we can genetically ablate this kinase specifically in meiotic cells. We are also investigating how H2AX phosphorylation precipitates chromatin-wide silencing.

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