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Draft:Nicholas Jarvis Proudfoot

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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[edit]

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[edit]

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[edit]

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.[1]

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.[2][3]

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.[4]

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.[5][6][7] Later on, work in his lab showed how in budding yeast transcription interference was prevented by failsafe termination mechanisms.[8] 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.[9][10][11][12] Sometimes overlapping with other groups his work identified many other sequence elements required for transcription termination, such as pause elements.[13][14][15][16][17][18] 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.[19] 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.[20][21][22][23][24][25][26][27] 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.[28][29][30][31] 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.[15][32][33][34][35][36]

Personal life[edit]

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:[edit]

Beit fellowship 1977.

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

References[edit]

  1. ^ Proudfoot, N. J.; Brownlee, G. G. (1976-09-16). "3' non-coding region sequences in eukaryotic messenger RNA". Nature. 263 (5574): 211–214. Bibcode:1976Natur.263..211P. doi:10.1038/263211a0. ISSN 0028-0836. PMID 822353. S2CID 4211839.
  2. ^ Baralle, F. E.; Shoulders, C. C.; Proudfoot, N. J. (October 1980). "The primary structure of the human epsilon-globin gene". Cell. 21 (3): 621–626. doi:10.1016/0092-8674(80)90425-0. ISSN 0092-8674. PMID 6254663. S2CID 54286568.
  3. ^ Proudfoot, N. J.; Baralle, F. E. (November 1979). "Molecular cloning of human epsilon-globin gene". Proceedings of the National Academy of Sciences of the United States of America. 76 (11): 5435–5439. doi:10.1073/pnas.76.11.5435. ISSN 0027-8424. PMC 411663. PMID 160554.
  4. ^ Higgs, D. R.; Goodbourn, S. E.; Lamb, J.; Clegg, J. B.; Weatherall, D. J.; Proudfoot, N. J. (Nov 24–30, 1983). "Alpha-thalassaemia caused by a polyadenylation signal mutation". Nature. 306 (5941): 398–400. Bibcode:1983Natur.306..398H. doi:10.1038/306398a0. ISSN 0028-0836. PMID 6646217. S2CID 4332750.
  5. ^ Proudfoot, N. J. (Aug 7–13, 1986). "Transcriptional interference and termination between duplicated alpha-globin gene constructs suggests a novel mechanism for gene regulation". Nature. 322 (6079): 562–565. Bibcode:1986Natur.322..562P. doi:10.1038/322562a0. ISSN 0028-0836. PMID 3736674. S2CID 4361633.
  6. ^ Greger, I. H.; Aranda, A.; Proudfoot, N. (2000-07-18). "Balancing transcriptional interference and initiation on the GAL7 promoter of Saccharomyces cerevisiae". Proceedings of the National Academy of Sciences of the United States of America. 97 (15): 8415–8420. Bibcode:2000PNAS...97.8415G. doi:10.1073/pnas.140217697. ISSN 0027-8424. PMC 26962. PMID 10890898.
  7. ^ Greger, I H; Proudfoot, N J (1998-08-17). "Poly(A) signals control both transcriptional termination and initiation between the tandem GAL10 and GAL7 genes of Saccharomyces cerevisiae". The EMBO Journal. 17 (16): 4771–4779. doi:10.1093/emboj/17.16.4771. ISSN 0261-4189. PMC 1170806. PMID 9707436.
  8. ^ Rondón, Ana G.; Mischo, Hannah E.; Kawauchi, Junya; Proudfoot, Nick J. (2009-10-09). "Fail-Safe Transcriptional Termination for Protein-Coding Genes in S. cerevisiae". Molecular Cell. 36 (1): 88–98. doi:10.1016/j.molcel.2009.07.028. ISSN 1097-2765. PMC 2779338. PMID 19818712.
  9. ^ Dye, Michael J.; Gromak, Natalia; Proudfoot, Nick J. (2006-03-17). "Exon tethering in transcription by RNA polymerase II". Molecular Cell. 21 (6): 849–859. doi:10.1016/j.molcel.2006.01.032. ISSN 1097-2765. PMID 16543153.
  10. ^ Dye, M. J.; Proudfoot, N. J. (March 1999). "Terminal exon definition occurs cotranscriptionally and promotes termination of RNA polymerase II". Molecular Cell. 3 (3): 371–378. doi:10.1016/s1097-2765(00)80464-5. ISSN 1097-2765. PMID 10198639.
  11. ^ Morlando, Mariangela; Ballarino, Monica; Gromak, Natalia; Pagano, Francesca; Bozzoni, Irene; Proudfoot, Nick J. (September 2008). "Primary microRNA transcripts are processed co-transcriptionally". Nature Structural & Molecular Biology. 15 (9): 902–909. doi:10.1038/nsmb.1475. ISSN 1545-9993. PMC 6952270. PMID 19172742.
  12. ^ Sousa-Luís, Rui; Dujardin, Gwendal; Zukher, Inna; Kimura, Hiroshi; Weldon, Carika; Carmo-Fonseca, Maria; Proudfoot, Nick J.; Nojima, Takayuki (2021-05-06). "POINT technology illuminates the processing of polymerase-associated intact nascent transcripts". Molecular Cell. 81 (9): 1935–1950.e6. doi:10.1016/j.molcel.2021.02.034. ISSN 1097-4164. PMC 8122139. PMID 33735606.
  13. ^ Gromak, Natalia; West, Steven; Proudfoot, Nick J. (May 2006). "Pause sites promote transcriptional termination of mammalian RNA polymerase II". Molecular and Cellular Biology. 26 (10): 3986–3996. doi:10.1128/MCB.26.10.3986-3996.2006. ISSN 0270-7306. PMC 1488997. PMID 16648491.
  14. ^ Dye, M. J.; Proudfoot, N. J. (2001-06-01). "Multiple transcript cleavage precedes polymerase release in termination by RNA polymerase II". Cell. 105 (5): 669–681. doi:10.1016/s0092-8674(01)00372-5. ISSN 0092-8674. PMID 11389836. S2CID 14984927.
  15. ^ a b Nojima, Takayuki; Dienstbier, Martin; Murphy, Shona; Proudfoot, Nicholas J.; Dye, Michael J. (2013-04-25). "Definition of RNA polymerase II CoTC terminator elements in the human genome". Cell Reports. 3 (4): 1080–1092. doi:10.1016/j.celrep.2013.03.012. ISSN 2211-1247. PMC 3644702. PMID 23562152.
  16. ^ West, Steven; Gromak, Natalia; Norbury, Christopher J.; Proudfoot, Nicholas J. (2006-02-03). "Adenylation and exosome-mediated degradation of cotranscriptionally cleaved pre-messenger RNA in human cells". Molecular Cell. 21 (3): 437–443. doi:10.1016/j.molcel.2005.12.008. ISSN 1097-2765. PMID 16455498.
  17. ^ West, Steven; Proudfoot, Nicholas J. (2009-02-13). "Transcriptional termination enhances protein expression in human cells". Molecular Cell. 33 (3): 354–364. doi:10.1016/j.molcel.2009.01.008. ISSN 1097-4164. PMC 2706331. PMID 19217409.
  18. ^ WEST, STEVEN; ZARET, KENNETH; PROUDFOOT, NICK J. (April 2006). "Transcriptional termination sequences in the mouse serum albumin gene". RNA. 12 (4): 655–665. doi:10.1261/rna.2232406. ISSN 1355-8382. PMC 1421085. PMID 16581808.
  19. ^ West, Steven; Gromak, Natalia; Proudfoot, Nick J. (2004-11-25). "Human 5' --> 3' exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites". Nature. 432 (7016): 522–525. Bibcode:2004Natur.432..522W. doi:10.1038/nature03035. ISSN 1476-4687. PMID 15565158. S2CID 4365304.
  20. ^ O'Sullivan, Justin M.; Tan-Wong, Sue Mei; Morillon, Antonin; Lee, Barbara; Coles, Joel; Mellor, Jane; Proudfoot, Nick J. (September 2004). "Gene loops juxtapose promoters and terminators in yeast". Nature Genetics. 36 (9): 1014–1018. doi:10.1038/ng1411. ISSN 1061-4036. PMID 15314641. S2CID 10241265.
  21. ^ Tan-Wong, Sue Mei; Wijayatilake, Hashanthi D.; Proudfoot, Nick J. (2009-11-15). "Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex". Genes & Development. 23 (22): 2610–2624. doi:10.1101/gad.1823209. ISSN 1549-5477. PMC 2779764. PMID 19933151.
  22. ^ Tan-Wong, Sue Mei; Zaugg, Judith B.; Camblong, Jurgi; Xu, Zhenyu; Zhang, David W.; Mischo, Hannah E.; Ansari, Aseem Z.; Luscombe, Nicholas M.; Steinmetz, Lars M.; Proudfoot, Nick J. (2012-11-02). "Gene loops enhance transcriptional directionality". Science. 338 (6107): 671–675. Bibcode:2012Sci...338..671T. doi:10.1126/science.1224350. ISSN 1095-9203. PMC 3563069. PMID 23019609.
  23. ^ Mischo, Hannah E.; Gómez-González, Belén; Grzechnik, Pawel; Rondón, Ana G.; Wei, Wu; Steinmetz, Lars; Aguilera, Andrés; Proudfoot, Nick J. (2011-01-07). "Yeast Sen1 helicase protects the genome from transcription-associated instability". Molecular Cell. 41 (1): 21–32. doi:10.1016/j.molcel.2010.12.007. ISSN 1097-4164. PMC 3314950. PMID 21211720.
  24. ^ Skourti-Stathaki, Konstantina; Proudfoot, Nicholas J.; Gromak, Natalia (2011-06-24). "Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination". Molecular Cell. 42 (6): 794–805. doi:10.1016/j.molcel.2011.04.026. ISSN 1097-4164. PMC 3145960. PMID 21700224.
  25. ^ Dhir, Ashish; Dhir, Somdutta; Borowski, Lukasz S.; Jimenez, Laura; Teitell, Michael; Rötig, Agnès; Crow, Yanick J.; Rice, Gillian I.; Duffy, Darragh; Tamby, Christelle; Nojima, Takayuki (August 2018). "Mitochondrial double-stranded RNA triggers antiviral signalling in humans". Nature. 560 (7717): 238–242. Bibcode:2018Natur.560..238D. doi:10.1038/s41586-018-0363-0. ISSN 1476-4687. PMC 6570621. PMID 30046113.
  26. ^ Gullerova, Monika; Proudfoot, Nick J. (March 2008). "Cohesin Complex Promotes Transcriptional Termination between Convergent Genes in S. pombe". Cell. 132 (6): 983–995. doi:10.1016/j.cell.2008.02.040. ISSN 0092-8674. PMID 18358811. S2CID 15010311.
  27. ^ White, Eleanor; Schlackow, Margarita; Kamieniarz-Gdula, Kinga; Proudfoot, Nick J; Gullerova, Monika (2014-05-11). "Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA". Nature Structural & Molecular Biology. 21 (6): 552–559. doi:10.1038/nsmb.2827. ISSN 1545-9993. PMC 4129937. PMID 24814348.
  28. ^ Grzechnik, Pawel; Gdula, Michal Ryszard; Proudfoot, Nick J. (2015-04-15). "Pcf11 orchestrates transcription termination pathways in yeast". Genes & Development. 29 (8): 849–861. doi:10.1101/gad.251470.114. ISSN 0890-9369. PMC 4403260. PMID 25877920.
  29. ^ Alén, Claudia; Kent, Nicholas A; Jones, Hannah S; O'Sullivan, Justin; Aranda, Agustı́n; Proudfoot, Nicholas J (December 2002). "A Role for Chromatin Remodeling in Transcriptional Termination by RNA Polymerase II". Molecular Cell. 10 (6): 1441–1452. doi:10.1016/s1097-2765(02)00778-5. ISSN 1097-2765. PMID 12504018.
  30. ^ Jones, Hannah S; Kawauchi, Junya; Braglia, Priscilla; Alen, Claudia M; Kent, Nicholas A; Proudfoot, Nick J (2007-01-28). "RNA polymerase I in yeast transcribes dynamic nucleosomal rDNA". Nature Structural & Molecular Biology. 14 (2): 123–130. doi:10.1038/nsmb1199. ISSN 1545-9993. PMC 6941936. PMID 17259992.
  31. ^ Morillon, Antonin; Karabetsou, Nickoletta; O'Sullivan, Justin; Kent, Nicholas; Proudfoot, Nicholas; Mellor, Jane (November 2003). "Isw1 Chromatin Remodeling ATPase Coordinates Transcription Elongation and Termination by RNA Polymerase II". Cell. 115 (4): 425–435. doi:10.1016/s0092-8674(03)00880-8. ISSN 0092-8674. PMID 14622597. S2CID 18369409.
  32. ^ Kamieniarz-Gdula, Kinga; Gdula, Michal R; Panser, Karin; Nojima, Takayuki; Monks, Joan; Wiśniewski, Jacek R; Riepsaame, Joey; Brockdorff, Neil; Pauli, Andrea (2018-12-09). "Selective roles of vertebrate PCF11 in premature and full-length transcript termination". dx.doi.org. doi:10.1101/491514. S2CID 196679231. Retrieved 2021-06-04.
  33. ^ Volanakis, Adam; Kamieniarz-Gdula, Kinga; Schlackow, Margarita; Proudfoot, Nick J. (2017-11-01). "WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription". Genes & Development. 31 (21): 2175–2185. doi:10.1101/gad.303677.117. ISSN 0890-9369. PMC 5749165. PMID 29196535.
  34. ^ West, S.; Proudfoot, N. J. (2007-11-21). "Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination". Nucleic Acids Research. 36 (3): 905–914. doi:10.1093/nar/gkm1112. ISSN 0305-1048. PMC 2241900. PMID 18086705.
  35. ^ Schlackow, Margarita; Nojima, Takayuki; Gomes, Tomas; Dhir, Ashish; Carmo-Fonseca, Maria; Proudfoot, Nick J. (January 2017). "Distinctive Patterns of Transcription and RNA Processing for Human lincRNAs". Molecular Cell. 65 (1): 25–38. doi:10.1016/j.molcel.2016.11.029. ISSN 1097-2765. PMC 5222723. PMID 28017589.
  36. ^ Nojima, Takayuki; Gomes, Tomás; Grosso, Ana Rita Fialho; Kimura, Hiroshi; Dye, Michael J.; Dhir, Somdutta; Carmo-Fonseca, Maria; Proudfoot, Nicholas J. (April 2015). "Mammalian NET-Seq Reveals Genome-wide Nascent Transcription Coupled to RNA Processing". Cell. 161 (3): 526–540. doi:10.1016/j.cell.2015.03.027. ISSN 0092-8674. PMC 4410947. PMID 25910207.
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