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Role of APC/C subunit APC7 in regulating the function of the APC/C E3 ubiquitin ligase


Project Description

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). APC/C E3 ligase activity is stimulated by the temporally coordinated recruitment of one of two related activator proteins, Cdc20 or Cdh1 to specific APC/C subunits; APC/C activators also serve in conjunction with APC/C subunits to bind substrates (1). The atomic structure of the APC/C holoenzyme, including all APC/C subunits has recently been determined by cryo-EM at 3.2 Å resolution (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, TIF1 gamma, 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 recent insights into APC/C structure and function we still know very little about how individual APC/C subunits function. The primary aim of this studentship therefore, is to characterize the role of the APC/C subunit APC7 in coordinating cell cycle progression. Specifically, this study aims to: (i) identify the APC7 interactome by mass spectrometry and characterise APC7-interactors as APC/C substrates or regulators; (ii) identify APC7 post-translational modifications (PTMs), e.g. phosphorylation, by mass spectrometry and identify the modifiers responsible for residue-specific PTMs; (iii) Adopt a structure-function approach to establish how specific modifications affect APC7 structure and function; (iv) Use live cell imaging to characterise role of specific APC7 modifications in cell cycle progression. Results of this study will be important in understanding the specific role of APC7 in the regulation of APC/C function.

Funding Notes

This 4 year studentship is competition funded by the BBSRC MIBTP scheme: View Website

Deadline: January 12, 2020
Number of Studentships available: 50
Stipend: RCUK standard rate (plus travel allowance in Year 1 and a laptop).
The Midlands Integrative Biosciences Training Partnership 2020 (MIBTP2020) is a BBSRC-funded doctoral training partnership between the Universities of Warwick, Birmingham, Leicester, Aston and Harper Adams. It delivers innovative, world-class research training across the Life Sciences to boost the growing Bioeconomy across the UK.
To check your eligibility to apply for this project please visit: View Website

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 gamma 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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