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Regulation of mitotic and meiotic chromosome function by different cohesin complexes


MRC London Institute of Medical Sciences (LMS)

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Dr E Martinez-Perez No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Cohesin, the complex that provides sister chromatid cohesion (SCC) to ensure correct chromosome segregation during cell division, belongs to a family of SMC (structural maintenance of chromosomes) proteins conserved from bacteria to humans (1). SMC complexes bind DNA to modify its topology, thus regulating chromosome structure throughout the cell cycle. In addition to providing SCC, cohesin plays key roles in DNA repair, in gene regulation by controlling genome folding, and in the formation of axial elements that promote pairing and recombination during meiosis. The core cohesin complex consists of two SMC subunits (SMC1 and SMC3) that interact at their hinge domain, plus a kleisin subunit (SCC1) that bridges the ATPase heads of the SMCs to form a tripartite ring structure. In addition, kleisins recruit regulatory subunits that control cohesin’s binding to DNA. Defects in cohesin function during somatic development cause Cornelia de Lange syndrome, a multi-system malformation syndrome characterised by cognitive and growth delays. Cohesin malfunction during meiosis results in aneuploidy, a leading cause of birth defects and miscarriages in humans. Studies in yeast showed that meiotic chromosome function requires substitution of the mitotic kleisin Scc1 by the meiosis-specific kleisin Rec8. Higher eukaryotes express additional meiosis-specific kleisins beyond REC8, including RAD21L in mammals and the highly identical and functionally redundant COH-3/4 in C. elegans (2). The basis for the functional differences between cohesin complexes differing in their kleisin subunit remains poorly understood.

We have recently shown how cohesin contributes to different aspects of meiotic chromosome function (3, 4, 5). The goal of the current project is to investigate the molecular mechanisms by which cohesin complexes differing in their kleisin subunit control the structure and function of mitotic and meiotic chromosomes in the nematode C. elegans. To achieve this, the project will combine functional in vivo studies, gene expression profiling, analysis of chromosome structure in 3D-intact nuclei by super-resolution microscopy, and single molecule approaches. This aspect of the project will involve a collaboration with the Aragon (Cell Cycle) and Rueda (Single molecule imaging) groups at the LMS, who recently developed methods to investigate the molecular activity of cohesin on DNA topology using optical tweezers (6). This project exploits the experimental advantages of C. elegans and state-of-the-art imaging and biophysical approaches to address a fundamental question of chromosome biology that is highly relevant to development and fertility in humans

To Apply: Please visit our website (https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/) to download an application form.

Funding Notes

This project is one of multiple available projects potentially funded by the MRC. If successful the studentship would cover all tuition fee payments and includes a tax-free stipend amounting to £21,000pa (paid in monthly installments directly to the student) for 3.5 years.

This project is direct funding available for UK/EU students only.

References

Hassler M, Shaltiel IA, and CH Haering (2018). Towards a unified model of SMC complex function. Curr Biol 28: R1266.

Ishiguro K-i (2019). The cohesin complex in mammalian meiosis. Genes Cells 24: 6.

Ferrandiz N, Barroso B, Telecan O, Shao N, Kim H-M, Testori S, Faull P, Cutillas P, Snijders AP, Colaiácovo MP and E. Martinez-Perez (2018). Spatiotemporal regulation of Aurora B recruitment ensures cohesion release during oocyte meiosis. Nat Commun 9: 838.

Crawley, O., Barroso, C., Testori, S., Ferrandiz, N., Silva, N., Castellano-Pozo, M., Jaso-Tamame, A.L., and Enrique Martinez-Perez (2016). Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes. eLife, 5: e10851.

Castellano-Pozo M, Pacheco S, Sioutas G, Jaso-Tamame AL, Dore MH, and E Martinez-Perez (2019). Reactivation of chromosome signalling induces reversal of the meiotic program. bioRxiv 754341.

Gutierrez-Escribano P, Newton MD, Llauro A, Huber J, Tanasie L, Davy J, Aly I, Aramayo R, Montoya A, Kramer H, Stigler J, Rueda D, and L Aragon (2019). A conserved activity for cohesin in bridging DNA molecules. bioRxiv 757286.
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