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Controlling cell cycle entry to maintain a stable genome in human cells

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  • Full or part time
    Dr A Barr
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

After cell division, individual cells can either re-enter the cell cycle and proliferate, or exit the cell cycle and become quiescent. Quiescent cells remain primed to resume proliferation upon receiving appropriate cues and cell cycle re-entry is tightly controlled during normal development and tissue homeostasis. Defective control of proliferation-quiescence decisions can lead to diseases such as fibrosis and cancer. Despite this, how cells enter, maintain and exit quiescent states is poorly understood at the molecular level.

One of the goals of our lab is to understand how human cells make the decision between proliferation and quiescence in response to intrinsic DNA damage and how this contributes to maintaining genome stability. We previously showed that intrinsic DNA damage incurred during DNA replication in the mother cell can determine the outcome of the proliferation-quiescence decision in daughter cells. This discovery was made using CRISPR/Cas9-mediated genetic engineering to fluorescently label cell cycle proteins, followed by quantitative, long-term, live, single-cell imaging to determine how the dynamic interplay of protein expression and activity determines cell fate. This has proved to be a powerful approach and by combining these experiments with mathematical modelling, molecular biology and genetics we can determine how molecular networks control proliferation-quiescence decisions. Ultimately, we hope to use this information to understand how these networks are perturbed to drive the continuous proliferation of cancer cells.

For further details please see website: https://lms.mrc.ac.uk/research-group/cell-cycle-control/
www.barrlab.com
or email: [Email Address Removed]

Funding Notes

This project is competition funded for students worldwide.

If successful the student would receive full tuition fee payment for 3.5 years as well as a tax free stipend amounting to £21,000pa paid in monthly instalments for the duration of their studentship.

Whilst Overseas Students are eligible, funding is more limited so only exceptional OS students will be considered.

References

Barr AR*1, Cooper S*, Heldt FS*, Butera F, Stoy H, Mansfeld J, Novak B, Bakal C1 (2017), DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nature Communications, Mar 20; doi: 10.1038/ncomms14728.

Heldt FS*, Barr AR*, Cooper S, Bakal C, Novak B (2018) A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells. PNAS Mar 6;115(10):2532-2537. Doi: 10.1073/pnas.1715345115.

Barr AR, Heldt FS, Zhang T, Bakal C, Novak B (2016), A dynamical framework for the all-or-none G1/S transition. Cell Systems, Jan 27; 2(1):27-37.

Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, Giltnane J, Arca Lacap J, Crocker L, Young A, Pearson A, Herrera-Abreu MT, Bakal C, Turner NC (2017), Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer. Clinical Cancer Research, Sep 15;23(18):5561-5572.



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