Department of Biochemistry
Molecular and Structural Biology Laboratory of Professor Sir Tom Blundell FRS
Applications are invited for a postdoctoral research associate in cryo-EM to join the Blundell laboratory at the University of Cambridge, Department of Biochemistry, Central Cambridge. The successful candidate will work on a project funded by a Wellcome Trust Investigator Award. The appointment will begin optimally from 1 October 2019 and will be initially for 18 months.
Research Summary: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) are the two major pathways of DNA double-strand break (DSB) repair in human cells. The aim of the research is to understand how NHEJ repairs DSBs directly without a DNA template but with maximal selectivity. Biochemical, structural and functional studies of individual components and complexes involved in NHEJ, carried out in the lab and elsewhere, suggest that several mechanisms operate throughout synapsis, end processing and ligation to maintain correct colocalisation of components over time. These are: (i) a stage provided by Ku-heterodimer interacting with DSBs supporting DNA-PKcs, PAXX amongst others; (ii) a second stage, DNA-PKcs, which links the kinase with DNA, Ku and the nuclease Artemis; (iii) a temporary scaffold, which facilitates repair operations, constructed from XRCC4-XLF filaments, assembling to bridge Ku bound at DSB ends. (iv) a string provided by Artemis C-terminal extension, which is intrinsically disordered, but includes short linear “epitopes” that recognise DNA PKcs and LigIV, and keeps components close by. The specific objective is to use cryo-EM to study the role of Artemis, both the nuclease component in preparing the DNA ends for ligation and the C-terminal extension in providing co-localisation at the correct time in order to mediate efficient DSB repair.
Duties: The successful candidate should have previous experience in molecular biology, biochemistry, cryo-EM and biophysical methods, most importantly with previous research in the area of complex multi-protein systems in cell regulation. The post-doctoral will be responsible for guiding the work on cryo-EM for the research team comprising two further post-doctoral researchers and a PhD student to achieve the research vision of this Wellcome Trust Investigator Award. The targets in this study are complex and large, for example DNA PKcs, which has over 4,000 amino acids, and Artemis, which has both nuclease activity and a region involving intrinsic disorder and binding regions for other components involved in DNA repair. The successful candidate must have a PhD or is about to complete a PhD and have hands-on knowledge of recent developments in cryo-EM techniques, experimental and computation for data processing, for defining high resolution structures.
Fixed-term: The funds for this post are available for 18 months in the first instance.
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Applicants should apply sending a CV, including a short statement of previous research and publications as well as the names of three referees who are established members of a university research institute or other research institution. Informal enquiries can be directed to Professor Sir Tom Blundell – firstname.lastname@example.org.
Please quote reference PH19955 on your application and in any correspondence about this vacancy.
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About Department of Biochemistry, University of Cambridge
The Department of Biochemistry is a member of the School of the Biological Sciences and one of the largest departments in the University of Cambridge. The Department is especially strong in research with investigators of international standing in a wide range of disciplines including structural biology, molecular enzymology, cell signalling and control of gene expression, molecular microbiology, plant molecular biology and bioenergy, cancer and cardiovascular biology. We also have a strong cohort of independent research fellows with funding from the Wellcome Trust, British Heart Foundation, BBSRC and MRC. The Department houses multiple core facilities funded by Wellcome Trust, BBSRC and MRC to support modern biomolecular research, including 800MHz NMR, state-of-the-art X-ray crystallography, protein chemistry, mass spectrometry, metabolomics and advanced services for protein and nucleic acid sequencing. In collaboration with the Department of Genetics we have also established the Cambridge Systems Biology Centre, which hosts genomics, proteomics and associated bioinformatics. We also participate in the Wellcome Trust-MRC Cambridge Stem Cell Institute , the Cambridge Cancer Centre and other major research initiatives.