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Role of APC/C subunit post-translational modifications on the function of the APC/C in mitosis


   Institute of Cancer and Genomic Sciences

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The APC/C is a large macromolecular E3 ubiquitin ligase, that, through targeting protein substrates for polyubiquitylation and 26S proteasome-mediated degradation coordinates the progression of cells through mitosis (1, 2). Recent evidence indicates that APC/C phosphorylation plays a critical role in its regulation; CDK1-dependent phosphorylation of APC3 and APC1 allows for structural changes in the APC/C complex that facilitates binding of Cdc20 to the APC/C (3).

Previous work from our laboratory has established that APC/C subunits, APC5 and APC7 associate with CBP/p300 acetyltransferases and stimulate their activity (4), whilst the transcriptional repressor, TIF1g, regulates progression through mitosis by associating with APC7 and modulating the activity of APC/C-Cdc20 (5). We have also shown that that the DNA damage response (DDR) protein, MDC1 regulates APC/C-Cdc20 activity during mitosis by promoting Cdc20 association with the APC/C (6), and the DDR protein 53BP1, is both a regulator and substrate of the APC/C, and serves to ensure genomic stability in response to mitotic stress (7).

Despite these studies and recent insights into the function of APC3 and APC1 phosphorylation, the role of post-translational modifications on the function of other APC/C subunits remains to be determined. The primary aim of this studentship therefore, is to characterize the role of APC/C subunit post-translational modifications in the regulation of APC/C function.


Funding Notes

Self-funded studentship
For further information contact Andy Turnell:

References

(1) Peters JM. The anaphase promoting complex/cyclosome: a machine designed to destroy (2006) Nat Rev Mol Cell Biol. 7:644-56; (2) Chang L et al. (2015). Atomic structure of the APC/C and its mechanism of protein ubiquitination Nature 522:450-454. (3) Fujimitsu K et al. (2016) Cyclin-dependent kinase 1-dependent activation of APC/C ubiquitin ligase. Science 352:1121-1124. (4) Turnell AS et al. (2005) The APC/C and CBP/p300 cooperate to regulate transcription and cell-cycle progression. Nature 438:690-695. (5) Sedgwick GG et al. (2013) Transcriptional Intermediary Factor 1 binds to the Anaphase-Promoting Complex/Cyclosome and promotes mitosis. Oncogene 32: 4622-4633. (6) Townsend K et al. (2009) MDC1 regulates mitotic progression. J. Biol. Chem. 284:33939-48. (7) Kucharski TJ et al (2017) Reciprocal regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome is required for genomic stability in response to mitotic stress. Cell Rep. 18(8):1982-1995.

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