Draft:Nicholas Jarvis Proudfoot

Nicholas Jarvis Proudfoot (born 6 June 1951), is a British-American molecular biologist and geneticist who made foundational discoveries on how messenger RNA is made and processed to maintain normal cellular gene expression.

Early Life and Education
Nick Proudfoot was born in Evanston (Chicago, Illinois) as second of three sons to Malcolm Jarvis Proudfoot (American) and Mary Proudfoot (nee McDonald, British). After the death of his father in 1956, Nick moved with his remaining family to Oxford and was educated in various boarding schools in southern England. He studied Biochemistry at London University at Bedford College and then enrolled at Cambridge University, King’s College, for his doctoral studies at the Laboratory of Molecular Biology (LMB) in Cambridge under the guidance of George Brownlee in Fred Sanger’s section of LMB. This was at a time when Fred Sanger and George Brownlee worked out various techniques to sequence RNA and DNA and restriction enzymes were just about to become available.

Career
During the work leading towards his PhD Thesis at the LMB, Nick Proudfoot discovered in 1976 the poly(A) signal that marks messenger RNA (mRNA) molecules for termination of transcription and proposed this signal’s importance for mRNA biogenesis.

During his postdoctoral time in the LMB and in the lab of Tom Maniatis in Caltech and Harvard, Nick Proudfoot cloned and sequenced some of the first genes from mRNA isolations (see scientific Achievements section).

Returning to the UK, Nick Proudfoot was recruited to the Sir William Dunn School at Oxford University headed by Henry Harris to join the newly established Chemical Pathology Unit with Tito Baralle under the lead of George Brownlee. He also became a fellow and tutor at Brasenose College Oxford where he taught Biochemistry and Molecular Biology.

Here he was appointed the Brownlee-Abraham Chair of Molecular Biology at the Dunn School of Pathology at Oxford University up to October 2020 (now an emeritus lab head at the Dunn School).

Scientific Achievements
At the LMB Nick Proudfoot was tasked to complementing attempts by George Brownlee and Cesar Milstein to isolate and sequence immunoglobulin mRNA from a B-cell cancer cell line. Using oligo(dT) affinity purified globin and immunoglobulin RNA and oligo(dT) as primer, Nick used E. Coli DNA polymerase with Manganese to copy the mRNA into complementary (c ) DNA using radioactive nucleotides (32P-labelled UTP). Using this technique, Nick Proudfoot was able to make the first reported cDNA copies of six different RNA molecules and sequence their 3’ ends. He realised that protein sequence was followed by 3’ non-coding sequence (now called the 3’ un-translated region) and that all of his six mRNA had a poly(A) containing sequence, which he coined the poly(A) signal.

During his postdoctoral time at the LMB Nick Proudfoot collaborated with Francesco (Tito) Baralle to generate probes against globin genes. Tito Baralle employed solid phase synthesis of oligonucleotides that could then be used to prime E. Coli polymerase cDNA synthesis at any position. Using an in-house preparation of the restriction enzyme HindIII to digest genomic DNA and 20L pizza-tray agarose gels to separate these fragments by size, their probes helped to isolate a globin gene. With different new tricks emerging in different labs all over the world, they were able to clone this gene (embryonic epsilon-globin) into a phage vector and sequence it using the plus and minus technique developed by Fred Sanger.

Nick Proudfoot continued his postdoctoral time cloning more genes with Tom Maniatis in Caltech and Harvard for two years.

In Oxford he initially continued to characterise globin genes. Together with Doug Higgs in the Weatherall Institute he established that some thalassemia patients that couldn’t produce alpha-globin harboured a single point mutation in the alpha-globin gene’s poly(A) signal. This proved the importance of the poly(A) signal for mRNA biogenesis and gene expression.

Nick also showed that failure to terminate RNA polymerase II transcription blocks transcription of downstream genes by occluding their promoter, a process called transcriptional interference. Later on, work in his lab showed how in budding yeast transcription interference was prevented by failsafe termination mechanisms. Nick Proudfoot’s laboratory continued to study transcription termination and co-transcriptional RNA processing steps and contributed to or established many accepted concepts in gene expression. His lab showed that splicing occurs co-transcriptionally and that intronic miRNAs are also co-transcriptionally produced. Sometimes overlapping with other groups his work identified many other sequence elements required for transcription termination, such as pause elements. His laboratory’s work provided the first proof for the torpedo model of transcription termination in mammalian cells by showing that the exonuclease Xrn2 is required for poly(A) signal dependent termination of transcription. He also brought the concept of gene-loops into the lime-light of scientific discussion and contributed important elements to the concept of co-transcriptional RNA-DNA hybrid formation and pathological RNA. Using budding or fission yeast as model systems, his laboratory genetically identified many factors involved in transcription termination and helped characterise non-coding RNA biogenesis. He transferred the knowledge gained in this model system back to the humans, always looking to integrate all aspects of chromosome biology into a coherent picture of how RNA transcription is regulated in eukaryotes.

Personal life
Nick Proudfoot is married to Anna Semple Proudfoot who accompanied Nick on his scientific journeys and is a prized and highly published Italian linguist. Anna and Nick have two sons (Malcolm and Alex). Nick Proudfoot is a keen musician, singing and playing the French horn in various ensembles.

Awards and honours:
Beit fellowship 1977.

EMBO Member from 1982 and Fellow of the Royal Society from 1995.