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Stephen C. West

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Stephen West
Stephen West
Born (1952-04-11) 11 April 1952 (age 72)
Hessle, England, United Kingdom
NationalityBritish
AwardsFRS (1995)
FMedSci (2000)
Royal Medal (2022)
American Academy of Arts and Sciences (2021)
National Academy of Sciences (2016)
Louis-Jeantet Prize for Medicine (2007)[1]
The Genetics Society Medal (2012)
Cancer Research UK Lifetime Achievement Prize (2018)
Scientific career
FieldsDNA recombination and repair
InstitutionsFrancis Crick Institute

Yale University

Newcastle University

Stephen Craig West FRS (born 11 April 1952) is a British biochemist and molecular biologist specialising in research on DNA recombination and repair. He is known for pioneering studies on genome instability diseases including cancer. West obtained his BSc in 1974, and his PhD in 1977, both from Newcastle University. He is currently a Principal Group Leader at the Francis Crick Institute in London. He is an honorary Professor at University College London, and at Imperial College London. In recognition of his work he was awarded the Louis-Jeantet Prize for Medicine in 2007, is a fellow of the Royal Society, the Academy of Medical Sciences, an International Member of the National Academy of Sciences, and an International Honorary Member of the American Academy of Arts and Sciences. He received the 2022 Royal Medal for 'discovering and determining the functions of key enzymes that are essential for DNA recombination, repair and the maintenance of genomes'.

Early life and education

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Stephen West was born on 11 April 1952 in Hessle, Yorkshire, to Joseph Clair West, a fishbuyer, and Louise West. Although he came from a working-class background, he did well enough at his local school (Hessle High School) to go to Newcastle University where he studied Biochemistry. He graduated with a BSc in 1974, and stayed in Newcastle to complete his PhD in 1977. His thesis advisor was Peter Emmerson.

Career

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During his PhD work, he became interested in how cells recombine their DNA and use recombination for DNA repair. In 1977, he identified ‘protein X’ as the elusive RecA protein, which is essential for recombination and repair in bacteria. After finishing his PhD, which he completed within three years, he moved to the United States to join the group led by Paul Howard-Flanders, one of the early pioneers in the field of DNA repair. In 1985, West moved back to the United Kingdom and established his own group at the Imperial Cancer Research Fund's laboratories in South Mimms in Hertfordshire, which subsequently became known as Cancer Research UK. His colleagues at Clare Hall laboratory included the Nobel Prize winners Tim Hunt and Tomas Lindahl. In 2016, his laboratory moved to the new Francis Crick Institute in London.

Research

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Highlights of research

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In the Howard-Flanders group at Yale University, West purified and characterised RecA protein, and in doing so discovered many key aspects relating to the way that cells mediate DNA-DNA interactions and strand exchange. Parallel studies were carried out in the groups of Charles Radding (also at Yale University) and Robert Lehman (Stanford University). These three laboratories provided the groundwork for our current understanding of the enzymatic mechanisms of recombination.

After moving to the UK in 1985, West continued his work in bacterial systems, and set about trying to identify cellular proteins capable of resolving recombination intermediates. He identified RuvC as the first cellular enzyme that resolves recombination intermediates and characterised how this nuclease cuts Holliday junctions. He was also the first to show that RuvA and RuvB are motor proteins that mediate Holliday junction branch migration. His biochemical studies were compounded by genetic work from the laboratory of Robert Lloyd (University of Nottingham).

West’s laboratory then moved into eukaryotic systems, where he discovered eukaryotic Holliday junction resolvases (yeast Yen1 and human GEN1). The identification of GEN1 was the culmination of 18 years of research, and opened up the field to allow a genetic analysis of the pathways by which recombination intermediates are processed. Present understanding indicates that there are three distinct pathways of Holliday junction processing in human cells involving BLM-topoIIIα-RMI1-RMI2 (BTR), SLX1-SLX4-MUS81-EME1-ERCC1-XPF (SMX) and GEN1. His laboratory discovered that the Holliday junction resolvase activities of MUS81 and GEN1 are regulated so that they act late in the cell cycle to ensure chromosome segregation.

In addition to the discovery of cellular Holliday junction resolvases, West was the first to purify the human RAD51 protein (the eukaryotic ortholog of RecA), and to show that it promotes homologous pairing and strand exchange reactions similar to those mediated by RecA. In addition, he purified and then visualised the BRCA2 breast cancer tumour suppressor, showing that it acts as a molecular chaperone for the association RAD51 with DNA. His laboratory also discovered that Aprataxin, which is defective in a progressive neurological disorder known as Oculomotor apraxia, is a 5'-deadenylase that removes AMP from 5'-termini following abortive DNA ligation.

Recently his laboratory described the high resolution structure of the RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2) complex using cryo-electron microscopy, and defined its function in DNA repair and tumour avoidance. He also used cryo-EM and biochemistry to determine the mechanism of single strand DNA annealing by the RAD52 protein.

As it is clear that DNA repair plays a critical role in the maintenance of genome stability and cancer avoidance, West’s work is significant in terms of understanding the molecular basis of human disease. In particular his laboratory discovered that loss of a nucleotide pool scavenger known as DNPH1 sensitises cancer cells to olaparib, a drug that is currently in use in the clinic for the treatment of breast, ovarian and prostate cancers caused by inheritable mutations in BRCA1 or BRCA2. He is in great demand as an international speaker, and gives several keynote lectures each year as a fine communicator of the intricacies of DNA recombination and repair.

Other professional activities

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West has been on the editorial boards of a number of journals including e-Life (2014-2016), EMBO Journal (1996-2020) and EMBO Reports (2000-2022). He is currently on the editorial board of DNA Repair.

He has been a member of the Scientific Advisory Board of the Leibniz Institute on Aging, Fritz Lippman Institute, Jena, Germany, and is currently on the SABs of the Center for Chromosome Instability, University of Copenhagen, Denmark, the China Medical University (Taiwan), the Guangdong Key Laboratory of Genome Stability in Shenzhen, China, and the Max Planck Institute for Biochemistry, Martinsreid, Germany.

Steve currently serves on the Council of the Royal Society until 2027.

He is a serial conference organiser, having organised (or co-organised) more than 30 conferences throughout his career. For many years he has organised the biennial International Conference on ‘Mechanisms of Recombination’. The next meeting in the series will take place in Crete, Greece, in May 2025 and is supported by Fusion.

Honours and awards

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West has been recognised on a number of occasions for his research:

Publications

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West has published over 270 papers which have been cited more than 40,000 times. He has a H-index of 118.

References

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  1. ^ Louis-Jeantet Prize
  2. ^ "New Members 2021". American Academy of Arts & Sciences. Retrieved 23 April 2021.
  3. ^ National Academy of Sciences Members and Foreign Associates Elected, News from the National Academy of Sciences, National Academy of Sciences, 3 May 2016, retrieved 14 May 2016.
  4. ^ Louis-Jeantet Prize
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