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  BBSRC NLD Doctoral Training Partnership: DNA mechanics under the control of DNA damage


   Department of Biosciences

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  Dr Aakash Basu, Dr Laura Maringele  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Big strides in molecular biology have consistently been driven by discoveries of novel ways in which organisms encode information in DNA. The discovery that protein coding information is encoded via the genetic code ushered in the era of modern molecular biology. Subsequently, discoveries revealing how regulatory information is genetically encoded in special sequence motifs and in epigenetic modifications of DNA bases have all been the catalysts for dramatic advances in our understanding of fundamental life processes.

Continuing this story, our group has begun to reveal yet another fundamental way in which organisms encode information in DNA. We found that, in addition to the genetic code, there exists a “mechanical code”, i.e., a clear dependence of the local mechanical and structural properties of DNA on local sequence. As almost all DNA:protein interactions critical to life involve some mechanical distortion of DNA, they can therefore be regulated by sequence-dependent variations in the local mechanical compliance of DNA to accommodate distortions. We developed a novel next-generation DNA sequencing based technology called loop-seq to decipher the mechanical code and reveal how evolution has used it to encode regulatory information impacting chromatin organization and gene expression [1, 2].

Preliminary studies we have conducted suggest that the mechanical code is not immutable, but can be modulated by chemical alterations to DNA. This project will aim to (1) characterize how the mechanical code can be modulated by chemical damage to DNA, and (2) understand how, by altering the mechanical code itself, DNA damage can regulate critical processes, including its own repair. DNA damage occurs ubiquitously owing to replication errors, environmental factors, aging, or diseases like cancers. Thus understanding what affects the DNA repair pathway is of fundamental biological importance, and central to future therapeutic and engineering efforts at controlling DNA damage and DNA repair.

The project will involve building and using a novel version of loop-seq that reports on the impact of DNA damage on DNA mechanics. Its findings will be complemented by in vitro and in vivo studies of DNA damage and repair pathways. The student will gain broad skills pertaining to next-generation DNA sequencing technology, molecular biology, biochemistry, bioinformatics, and data science.

[1] “Measuring DNA mechanics on the genome scale”, Basu et. al., Nature, 589, 462 – 467 (2021)

[2] "Deciphering the mechanical code of the genome and epigenome”, Basu et. al., Nature Structural and Molecular Biology, 29, 1178 – 1187 (2022)

 HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·        a CV (including contact details of at least two academic (or other relevant) referees);

·        a covering letter – clearly stating your first-choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·        copies of your relevant undergraduate degree transcripts and certificates;

·        a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed].

The deadline for all applications is 12noon on Monday 22nd July 2024. 

Part-Time Study Options

All NLD DTP PhDs are available as part time or full time, with part time being a minimum of 50% of full time. Please discuss potential part time arrangements with the primary supervisor before applying to the programme.

Project CASE Status

This project is not a CASE project. While individual applicant quality is our overriding criterion for selection, the NLD DTP has a commitment to fund 8 CASE projects per year - as such, CASE projects may be favoured in shortlisting applicants when candidates are otherwise deemed to be equal or a consensus on student quality cannot be reached. 

Biological Sciences (4) Chemistry (6)

Funding Notes

BBSRC NLD DTP programme – starting October 2024. UKRI provide the following funding for 4 years: • Stipend (2024/25 UKRI rate £19,237) • Tuition Fees at UK fee rate (2024/25 rate £4,786) • Research support and training grant (RTSG). Note - UKRI funding only covers UK (Home) fees.


References

Measuring DNA mechanics on the genome scale, Nature, 589, 462 – 467 (2021).
Deciphering the mechanical code of the genome and epigenome, Nature Structural and Molecular Biology, 29, 1178 – 1187 (2022).
A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress, Mol Cell Biol 2023;43(5):185-199
Rif1 and Exo1 regulate the genomic instability following telomere losses, Aging Cell 2016 Jun;15(3):553-62
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