Dr Lori Passmore
Dr Lori Passmore is pleased to consider applications from prospective PhD students.
We use a hybrid approach to study the structure and function of multi-protein complexes. A major focus of the lab is on complexes involved in the regulation of mRNA polyadenylation and deadenylation. Eukaryotic genes are normally transcribed as pre-mRNAs that must be processed before they are exported from the nucleus and translated into proteins. The 3´-end of the pre-mRNA is cleaved and a poly(A) tail is added to the new 3´-end. Several protein factors are required to co-ordinate the 3´-end processing reactions, and to facilitate communication with the transcription and splicing machinery. In yeast this includes a large multi-protein complex called Cleavage and Polyadenylation Factor (CPF). The poly(A) tail is required for export of the mRNA into the cytoplasm. It also enhances mRNA stability and stimulates translation, and its length can be regulated to influence these functions. For example, shortening of the poly(A) tail can decrease the efficiency of translation to control gene expression, and is the first step in mRNA turnover. The major deadenylase activities are found within the evolutionarily conserved, 1MDa Ccr4-Not complex and Pan2-Pan3. By understanding the structure and mechanisms of these protein complexes, we will gain insight into the regulation of mRNA polyadenylation and gene expression.
A second focus of the lab is the Fanconi anaemia (FA) core complex. This multi-subunit E3 ubiquitin ligase acts in a pathway that repairs DNA damage caused by DNA crosslinks. Mutation of the genes encoding subunits of the FA core complex results in Fanconi anaemia which includes developmental abnormalities, bone marrow failure and cancer predisposition. We are studying the complex using biochemical reconstitution and structural biology to understand the molecular basis for its function.
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Tang TTL, Stowell JAW, Hill CH, Passmore LA (2019) The intrinsic structure of poly(A) RNA determines the specificity of Pan2 and Caf1 deadenylases. Nature Struct Mol Biol 26: 433-442
Hill CH, Boreikaitė V, Kumar A, Casañal A, Kubík P, Degliesposti G, Maslen S, Mariani A, von Loeffelholz O, Girbig M, Skehel M, Passmore LA (2019) Activation of the endonuclease that defines mRNA 3ʹ-ends requires incorporation into an 8-subunit core cleavage and polyadenylation factor complex. Mol Cell 73, 1217–1231
Webster MW, Chen YH, Stowell JAW, Alhusaini N, Sweet T, Graveley BR, Coller J, Passmore LA (2018) mRNA deadenylation is coupled to translation rates by the differential activities of Ccr4-Not nucleases. Mol Cell 70:1089-1100.e8.
Casañal A, Kumar A, Hill CH, Easter AD, Emsley P, Degliesposti G, Gordiyenko Y, Santhanam B, Wolf J, Wiederhold K, Dornan GL, Skehel M, Robinson CV and Passmore LA (2017) Architecture of eukaryotic mRNA 3′-end processing machinery. Science 348: 1056-1059
Wolf J, Valkov E, Allen MD, Meineke B, Gordiyenko Y, McLaughlin SH, Olsen TM, Robinson CV, Bycroft M, Stewart M & Passmore LA (2014) Structural basis for binding of Pan3 to Pan2 and its function in mRNA recruitment and deadenylation. EMBOJ 33(14):1514-26
Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ & Passmore LA (2014) The genetic and biochemical basis of FANCD2 monoubiquitination. Mol Cell 54(5): 858-869.
Russo CJ & Passmore LA (2014) Ultrastable gold substrates for electron cryomicroscopy. Science 346(6215):1377-1380