Structural Biochemistry of Meiotic Mechanisms

John Weir

JWeir Ansorg Portraits crop2red
  • Research assistant 2004-2006 MRC-LMB, Cambridge
  • PhD 2006-2011 EMBL, Heidelberg and MPI Biochemistry, Martinsried
  • Postdoc 2011-2016 MPI Molecular Physiology, Dortmund
  • Group leader at the FML from 2017

Research Interest

Meiosis is a specialised form of cell division, and the starting point of sexual reproduction, that results in the formation of haploid gametes from a diploid cell. Meiosis is biphasic; Meiosis I segregates the homologous chromosomes (one from each parent), meiosis II then separates the sister chromatids from one another. The process of meiosis is essential to maintain ploidy through the production of haploids, but also contributes to genetic diversity through the intrinsic mechanism that connects homologous chromosomes.

In order to segregate homologous chromosomes, they first must be linked. The process starts with the cell making programme double-strand breaks in its own genome. These breaks are then repaired via homologous recombination with the homologous chromosome. Some break repairs will result in crossover formation, which links the homologs in conjunction with cohesin. Double-strand break initiation and cross over formation are controlled through a dazzling array of enzymatic and structural factors. While the factors involved in these processes have been identified, there is limited understanding of the molecular mechanisms. Our lab exploits the power and flexibility of recombinant biochemical reconstitution together with hybrid structural biology and yeast genetics to provide clear and novel insights into the events in early meiosis.

 

 

  • Weir IMPRS Figure
    click to enlarge

During the meiotic program a diploid progenitor cell gives rise to four haploid gametes (top, left to right). During meiosis I, homologous chromosomes must be linked. In order to do this the cell makes breaks in its own genome (yellow flash). The break formation is carefully regulated and requires a large number of factors (inset lower left). Some breaks are then further processed to a cross over (inset lower right) which, together with cohesin, provides the link between homologous chromosomes.

Available PhD Projects

Project 1: Control of meiotic double strand break formation by the axis proteins.

Project 2: Regulation of meiotic cross over formation through the synaptonemal complex.

Selected Reading

1)  Weir JR*, Klare K*, Faesen A* et al. (2016). Insights from biochemical reconstitution into the architecture of human kinetochores. Nature 537:249-253.

2)  Klare K*, Weir JR* et al. (2015). CENP-C is a blueprint for CCAN assembly within human kinetochores. J. Cell Biol. 210:11-22.

3)  Falk S*, Weir JR*, et al. (2014). The molecular architecture of the TRAMP complex reveals the organization and interplay of its two catalytic activities. Mol. Cell 55:856-67.

* Denotes shared first authorship