Disentangling the Myc:Max transcriptional network

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2022 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

This 4-year PhD studentship is offered in Dr Gerard Evan’s Group based at the Francis Crick Institute (the Crick).

The Myc proteins are heterodimeric bHLHZip transcription factors that serve as obligate regulators of cell proliferation. Myc deregulation is implicated in many, perhaps all cancers. Myc proteins heterodimerize with their partner protein Max via their complementary bHLHZip dimerization domains to bind promoter and enhancer CACGTG E-box elements and activate expression of their many target genes. However, Max is also a heterodimeric partner for the Mxd/Mnt proteins. Mxd:Max heterodimers bind the same E-boxes as Myc:Max but act as potent transcriptional repressors. Hence, Myc, Max and Mxd potentially reside in an integrated “pushmepullyou” antagonistic network, so they have the potential to act as Myc antagonists. To add further complexity, Mxd proteins themselves share an additional dimerization partner with the MONDO family proteins, which regulate cell metabolism. Many have suggested that the interconnectedness of the Myc:Max:Mxd:Mxi:MONDO (M5) network is essential for Myc’s physiological and pathological functions, in particular its role in normal and cancer cell growth, metabolism, proliferation and reorganization of extracellular matrix. Indeed, inactivation of Mxd family proteins has been observed in many cancers, suggesting that Mxd proteins do serve to restrain Myc activity. By its nature, however, an integrated network is difficult to untangle because perturbation of one part necessarily impacts all the other interconnected components. Hence, to disentangle the network’s functionality, we have constructed designed mutant forms of Myc and Max with altered dimerization specificities by replacing the Myc and Max Zip dimerization domains with those from unrelated yeast proteins. These MycRTG3 and Max RTG1 mutants heterodimerize with each other but not with any other members of the M5 network. The project will use these unique specificity swap Myc and Max mutants to ascertain determine what role, if any, the M5 network plays in Myc’s pivotal activities driving cell growth, cell metabolism, cell cycle, cell proliferation and cancer.

Candidate background

The project will suit someone who wants to combine molecular biology and state-of-the-art switchable genetic models to understand fundamental questions in cancer biology.

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘INSTITUTION WEBSITE’ LINK ABOVE) BY 12:00 (NOON) 11 November 2021. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.