Obituary15 February 2021free access Richard Jackson (1940–2020) - A towering presence in translation Nancy Standart Corresponding Author Nancy Standart [email protected] orcid.org/0000-0001-5963-6255 University of Cambridge, Cambridge, UK Search for more papers by this author John Hershey John Hershey University of California, Davis, CA, USA Search for more papers by this author Michael B Mathews Michael B Mathews Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA Search for more papers by this author Nahum Sonenberg Nahum Sonenberg orcid.org/0000-0002-4707-8759 Department of Biochemistry, McGill University, Montreal, QC, Canada Search for more papers by this author Nancy Standart Corresponding Author Nancy Standart [email protected] orcid.org/0000-0001-5963-6255 University of Cambridge, Cambridge, UK Search for more papers by this author John Hershey John Hershey University of California, Davis, CA, USA Search for more papers by this author Michael B Mathews Michael B Mathews Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA Search for more papers by this author Nahum Sonenberg Nahum Sonenberg orcid.org/0000-0002-4707-8759 Department of Biochemistry, McGill University, Montreal, QC, Canada Search for more papers by this author Author Information Nancy Standart *,1, John Hershey2, Michael B Mathews3 and Nahum Sonenberg4 1University of Cambridge, Cambridge, UK 2University of California, Davis, CA, USA 3Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA 4Department of Biochemistry, McGill University, Montreal, QC, Canada *Corresponding author. E-mail: [email protected] The EMBO Journal (2021)40:e107551https://doi.org/10.15252/embj.2020107551 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Richard Jackson retirement dinner, Pembroke College, Cambridge. Photo by RNA lab, 2009, used with permission. We write in memory of our dear colleague and friend Richard Jackson who died September 21, 2020, at the age of 80. Richard spent almost his entire distinguished career studying protein synthesis in the Department of Biochemistry at the University of Cambridge, following graduation there in 1962. His PhD was in the laboratory of Asher Korner where he overlapped with fellow students Tim Hunt and Tony Hunter, resulting in a thesis in 1966 on ribosomes and tRNA. It was a two-volume affair and led to a University edict that henceforth, theses were to be word limited. Even so, those who knew him, such as colleagues, editors, or reviewees, will recall that he was rarely limited for words thereafter. After a postdoctoral position in Geneva with Alfred Tissières, he re-joined the Department. Richard formally retired as Professor of RNA Biochemistry in 2007 but never really left, remaining very active in the Department as Emeritus Professor. Richard made numerous contributions to understanding the regulation of translation initiation of cellular and viral mRNAs, but the work that arguably had the broadest impact was technical in nature. In 1976, he and his PhD student Hugh Pelham described a highly efficient mRNA-dependent in vitro translation system. To remove endogenous mRNA, they optimized the treatment of the rabbit reticulocyte lysate (RRL) with micrococcal nuclease, subsequently inhibited with EGTA. This assay underpinned many fundamental studies of translation initiation, and with the advent of cloning coupled with in vitro transcription, it became an invaluable tool for investigators seeking to link genes to their protein products. In those more innocent days, Richard did not consider patents but helped to develop the reticulocyte lysate system, which remains a standard toolkit in many molecular biology labs, commercially. This and the subsequent coupled in vitro transcription–translation system benefited from the close collaboration with Tim Hunt with whom Richard shared a communal lab in the 70s and 80s. Richard recognized early the advantages of the rabbit reticulocyte system for dissecting the mechanism of translational control. Throughout his career, he and his co-workers exploited this system to good effect. Most notable was the identification of a crucial aspect of translation initiation with Tony Hunter. Following their observation of the transitory appearance of methionyl-tRNA (Met-tRNA) in complex with the 40S small ribosomal subunit, they were among the first to realize that in eukaryotes, as in prokaryotes, the initiation of protein synthesis is primed by a methionine residue supplied by a specialized tRNA. This isoform, now called Met-tRNAI, is distinct from Met-tRNAm, which supplies the amino acid internally in proteins. In the regulatory arena, with his PhD student Paul Farrell and Hans Trachsel, Richard laid the foundations of the unfolded protein response which underlies many features of eukaryotes’ reaction to stress. In the RRL, stress in the form of heme deprivation (disrupting hemoglobin synthesis) or the inclusion of double-stranded RNA (a product of viral infection) led to the same biochemical effect—phosphorylation of the eukaryotic initiation factor eIF2 on its alpha subunit. This constitutes a key cellular regulatory mechanism that permeates the response to disease, environmental, and genetic stressors. While most initiation in eukaryotes depends on the cap at the 5′ end of cellular mRNAs, cap-independent mechanisms also exist. Richard was a pioneer in the field of internal ribosome entry segment/site (IRES) translation. Unlike cellular and most viral mRNAs, picornavirus mRNA does not harbor a cap structure. The identification in the 5’ untranslated regions of picornavirus RNAs of extensive sequences that direct cap-independent IRES-dependent translation met with fierce criticism from some quarters, but Richard embraced the conclusions and decisively advanced the field by elucidating how IRESes act to recruit the ribosome. The determinants of initiation codon selection were analyzed in meticulous detail—a hallmark of all of Richard’s expansive work. With Ann Kaminski, Sarah Hunt, and Yoita Kafasla, he focused on the sequence and secondary structure of two different picornavirus IRES groups: the cardioviruses (encephalomyocarditis virus, EMCV) and enteroviruses (polio- and rhinoviruses). They demonstrated that the EMCV IRES places the ribosome directly onto the viral initiation codon, whereas in the case of the rhinovirus the ribosome lands upstream of the AUG and scans to reach it. The IRESs differ too in terms of trans-activating factors for cap-independent translation. Richard and colleagues discovered protein factors (IRES trans-activating factors, ITAFs) that enhance the function of the polio/rhinovirus IRES elements within the RRL system, including polypyrimidine tract-binding protein (PTB) and the RNA-binding protein UNR. Using directed hydroxyl radical probing and mass spectrometry, Richard's and Carol Robinson's laboratories showed that PTB stabilizes the three-dimensional fold of the EMCV IRES, while it stimulates poliovirus IRES activity by inducing initiation factor eIF4G binding. Key structural features of a third type of IRES from hepatitis C and pestiviruses were also elucidated. Richard's work also shed light on the important question of initiation of an open reading frame (ORF) when preceded by a short upstream ORF (uORF), present in about half of eukaryotic mRNAs. He and Tuija Pöyry devised an ingenious set of reporter constructs to assess re-initiation in vitro by exploiting the distinct properties of several viral IRESes vis-a-vis their translation initiation factor requirements. They showed that re-initiation requires the interaction between eIF4G/eIF3 and the ribosome translating the uORF being transiently maintained, rather than lost upon subunit joining. This model, considered somewhat speculative at the time, rationalized why most uORFs are shorter than 30 codons, and is compatible with eIF4G/eIF3 being bound to the solvent side of 40S. Some sixteen years later, the Teleman and Wolf laboratories validated in vivo that ribosomes do indeed retain eIF4G/eIF3 during early translation. Richard was a towering presence in the translation field, widely respected for the clarity and rigor of his experimental work and scientific writing. He was well-known (possibly even feared) at meetings for his incisive questions, invariably raised from the back of the lecture theater. A tall, almost gaunt figure, with a somewhat austere bearing, Richard could seem forbidding. But his colleagues and friends will remember the twinkle in his eyes, his dry wit, his kindness, and generosity. He managed to combine an encyclopedic knowledge of biochemistry with legendary powers of recall and one of the most untidy offices in the Department. Richard loved designing a clever experiment and working out its implications. He fought eloquently for his manuscripts and wrote many authoritative reviews and book chapters for the CSHL Translational Mechanisms and Control series. We hugely enjoyed assisting with his broader interests in translation, ranging from the role of the poly(A) tail to that of microRNAs, to ribosome profiling. Richard was thrilled to be elected a member of EMBO in 1991 and a Fellow of the Royal Society in 2006 alongside Nahum Sonenberg. Indeed, Richard joked at the time that they were like buses—you wait ages for an FRS in translation and then two come at once. He was an incredibly supportive and friendly colleague and mentor, giving those in his laboratory a great deal of independence. Richard was invariably understated and modest, with a remarkable joie de vivre, dancing late into the night at Cold Spring Harbor or Heidelberg Translation meetings, and hosting annual summer laboratory parties at his house. Richard was no doubt intrigued by the COVID-19 pandemic being due to single-stranded RNA, albeit considerably longer and more complex than the viruses he studied. And he would surely have been delighted by the success of mRNA vaccines. Richard was utterly devoted to his wife Wiltrud, his daughters Bridget and Tina, and their children, who were with him at his peaceful end. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 40,Issue 6,15 March 2021This month's cover highlights the article Translational adaptation to heat stress is mediated by RNA 5-methylcytosine in Caenorhabditis elegans by Isabela Cunha Navarro, Eric A. Miska and colleagues. Despite the evolutionary conservation of several RNA modifications, their physiological functions remain largely unknown. Here, using Caenorhabditis elegans, the authors produced the first animal strain completely devoid of 5-methylcytosine in RNA. While this modification is not essential for development under standard conditions, it sustains normal fertility and efficiency of leucine UUG translation at higher temperatures. (Cover concept by the authors; illustration by Sandra Krahl) Volume 40Issue 615 March 2021In this issue RelatedDetailsLoading ...