• Structural Biochemistry of Meiosis

How are homologous chromosomes linked to one another during meiosis I? How is the machinery built and regulated?

We each have two copies of each chromosome, one from mum, and one from dad. These chromosomes are very similar to one another, and are known as homologs. When we produce gametes (i.e. sperm or egg) we need to halve the number of chromosomes in these cells, so that our children will inherit the correct number of chromosomes. This requires that the homologs are segregated away from each other properly. When this process goes awry, it can lead to chromosomal disorders such as trisomy 21.

In order to be segregated from each other the homologs first have to be linked, this is a challenge because homologous chromosomes are usually not associated with one another. A mechanism called homologous recombination (HR) exists, that can repair damaged DNA, copying the correct sequence from the homolog. During meiosis the cell make programmed double strand breaks (DSBs) in its own DNA which is then repaired by HR, which in turn result in crossover linkages between the homologs.

The location, timing and number of DSBs is tightly controlled, furthermore, not all DSBs are processed into crossovers. DNA break and crossover homeostasis is vital. Too many DSBs and genome integrity is compromised, likewise if DSBs are made in “forbidden” regions of the genome. Too few breaks and it will not be possible to generate the crossovers necessary to securely link homologs.

We aim to:

Biochemically reconstitute the DSB and crossover machinery on synthetic chromatin using recombinant proteins.

Determine how control mechanisms work by adding appropriate regulatory factors (e.g. kinases) to our reconstitutions.

Gain high resolution structural information using a combination of X-ray crystallography and cryo-electromicroscopy.

Test our findings in the budding yeast S. cerevisiae, which carries out meiosis in a remarkably similar way to mammals.

What I cannot create, I do not understand

Richard Feynman


Key Publications

  1. Pesenti ME, Prumbaum D, Auckland P, Smith CM, Faesen AC, Petrovic A, Erent M, Maffini S, Pentakota S, Weir JR, Lin YC, Raunser S, McAinsh AD, Musacchio A. Reconstitution of a 26-Subunit Human Kinetochore Reveals Cooperative Microtubule Binding by CENP-OPQUR and NDC80. Mol Cell. 2018 Sep 20;71(6):923-939.e10.
  2. Pentakota S, Zhou K, Smith C, Maffini S, Petrovic A, Morgan GP, Weir JR, Vetter IR, Musacchio A, Luger K. Decoding the centromeric nucleosome through CENP-N. elife. 2017 Dec 27;6. pii: e33442.
  3. Weir JR*, Faesen AC*, Klare K*, Petrovic A, Basilico F, Fischböck J, Pentakota S, Keller J, Pesenti ME, Pan D, Vogt D, Wohlgemuth S, Herzog F, Musacchio A. Insights from biochemical reconstitution into the architecture of human kinetochores. Nature. 2016 Sep 8;537(7619):249-253.
  4. Klare K*, Weir JR*, Basilico F, Zimniak T, Massimiliano L, Ludwigs N, Herzog F, Musacchio A. CENP-C is a blueprint for constitutive centromere-associated network assembly within human kinetochores. J Cell Biol. 2015 Jul 6;210(1):11-22.
  5. Falk S*, Weir JR*, Hentschel J, Reichelt P, Bonneau F, Conti E. The molecular architecture of the TRAMP complex reveals the organization and interplay of its two catalytic activities. Mol Cell. 2014 Sep 18;55(6):856-867.

see full publication list here

Future Plans

We aim to expand our biochemical reconstitutions to the extent where we can create meiotic crossover in a test tube using synthetic DNA. We will make increasing use of hybrid structural biology approaches, combining different methods to gain a most complete picture of the systems we are interested in. Equally we intend to expand beyond the use of yeast as a model organism and start to address phenomena specific to vertebrate and particularly human meiosis. In the long run, it is hoped that our work might be of use to clinicians who are helping people with fertility problems or those with genetic diseases.