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Survival pathways supporting BRCA1 function.


Project Description

Background: The genes involved in the most accurate form of DNA repair, homologous recombination, are needed for normal development and normal cellular recombination. In recent years it has become clear that the proteins have multiple functions that contribute to the outcomes of good DNA repair under different stress contexts.
We are particularly interested in one of the most significant DNA repair genes, BRCA1, which was first discovered due to its association with breast cancer. In recent years we have started to prise apart the subtly different functions encoded in this one gene and it is now clear that it performs at least three different functions. These functions are likely to contribute to its full role in promoting normal development and normal cellular processes, and one in particular is needed as cells are replicating, protecting the exposed DNA ends when replication stalls.
Objectives: In this project we will use cells in which we have disabled the replication fork protection function of the BRCA1. We aim to use genome-wide CRISPR-Cas9 based gene knock-out to examine what cellular pathways support cell survival in the absence of that one function.
Methods: The CRISPR screens include a bar-code based sequencing of cells to establish the identity of knocked-out genes, combined with pathway analysis to establish which cellular signalling pathways have been lost. The findings will be validated by specifically removing key nodes of the newly identified pathways using RNA silencing to establish that cells lacking the specific BRCA1 function specifically require the identified pathway nodes.
By these means we hope to understand how BRCA1 enables normal development and promotes critical cellular functions such as DNA replication.

Funding Notes

Candidates should have a biology, biochemistry or biomedical degree.
Candidates with a 1st class degree or laboratory experience will be at an advantage.
Candidates with evidence of strong mathematics/computing ability will be at a significant advantage.
This project is offered through the Midlands Integrative Biosciences Training Partnership please see the following link for details of eligability:
View Website

References

Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat Struct Mol Biol. 2016 Jul;23(7):647-55. doi: 10.1038/nsmb.3236. Epub 2016 May 30.

The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature. 2009 Dec 17;462(7275):886-90. doi: 10.1038/nature08593.

Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9 Nat Biotechnol. 2016 Feb;34(2):184-191. doi: 10.1038/nbt.3437. Epub 2016 Jan 18.

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