Stephen C West

Early life and education

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

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, 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.

Highlights of research

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, MUS81-EME1 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.

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. 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

West is on the editorial boards of a number of journals including e-Life (2014-2016), EMBO Journal and EMBO Reports.

He is a member of the Scientific Advisory Boards of the Leibniz Institute on Aging, Fritz Lippman Institute, Jena, Germany, the Center for Chromosome Instability, University of Copenhagen, Denmark, and the China Medical University (Taiwan).

He is a serial conference organiser, having organised (or co-organised) more than 30 conferences throughout his career. Currently, he is the organiser of the biennial International Conference on ‘Mechanisms of Recombination’. The next meeting in the series will take place in London in May 2018.

Honours and awards

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

Publications

West has published 250 papers and has been cited more than 25,000 times. Selected articles include:

1. WYATT, H.D.M., LAISTER, R.C., MARTIN, S.R., ARROWSMITH, C.H. and WEST, S.C. (2017) The SMX DNA repair tri-nuclease. Mol. Cell. 65, 848-860.
2. SHAHID, T., SOROKA, J., KONG, E., MALIVERT, L., McILWRAITH, M.J., PAPE, T., WEST, S.C. and ZHANG, X. (2014) Structure and mechanism of action of the BRCA2 breast cancer tumour suppressor. Nat. Struct. Mol. Biol. 21, 962-968
3. BLANCO, M.G, MATOS, J. and WEST, S.C. (2014) Dual control of Yen1 nuclease activity and cellular localization by Cdk and Cdc14 prevents genome instability. Mol. Cell. 54, 94-106.
4. WYATT, H.D.M., SARBAJNA, S., MATOS, J. and WEST, S.C. (2013) Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells. Mol. Cell. 52, 234-247.
5. WECHSLER, T., NEWMAN, S. and WEST, S.C. (2011) Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature 471, 642-646.
6. MATOS, J., BLANCO, M.G., MASLEN, S., SKEHEL, J.M. and WEST, S.C. (2011) Regulatory control of the resolution of DNA recombination intermediates during meiosis and mitosis. Cell 147, 158-172.
7. IP, S.C.Y., RASS, U., BLANCO, M.G., FLYNN, H.R., SKEHEL, J.M. and WEST, S.C. (2008) Identification of Holliday junction resolvases from humans and yeast. Nature, 456, 357-361.
8. McILWRAITH, M.J. and WEST, S.C. (2008) DNA repair synthesis facilitates RAD52-mediated second-end capture during DSB repair. Mol. Cell 29, 510-516.
9. AHEL, I., AHEL, D., MATSUSAKA, T., CLARK, A.J., PINES, J., BOULTON, S.J. and WEST, S.C. (2008) Poly(ADP-ribose)-binding zinc finger motif in DNA repair/checkpoint proteins. Nature 451, 81-85.
10. RASS, U., AHEL, I. and WEST, S.C. (2007) Defective DNA repair and neurodegenerative disease. Cell, 130, 991-1004.
11. CICCIA, A., LING, C., COULTHARD, R., YAN, Z., XUE, Y., MEETEI, A.R., LAGHMANI, E.H., JOENJE, H., McDONALD, N., DE WINTER, J.P., WANG, W. and WEST, S.C. (2007) Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol. Cell, 25, 331-343.
12. AHEL, I., RASS., U, EL-KHAMISY, S.F., KATYAL, S., CLEMENTS, P.M., MCKINNON, P.J., CALDECOTT, K.W. and WEST, S.C. (2006) The neurodegenerative disease protein Aprataxin resolves abortive DNA ligation intermediates. Nature, 443, 713-716.
13. ESASHI, F., CHRIST, N, GANNON, J., LIU, Y., HUNT, T., JASIN, M. and WEST, S.C. (2005) CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598-604.
14. TARSOUNAS, M., MUNOZ, P., CLAAS, A., SMIRALDO, P.G., PITTMAN, D.L., BLASCO, M.A. and WEST, S.C. (2004). Telomere maintenance requires the RAD51D recombination/repair protein. Cell 117, 337-347.
15. LIU, Y., MASSON, J.-Y. SHAH, R., O’REGAN, P. and WEST, S.C. (2004) RAD51C is required for Holliday junction processing in mammalian cells. Science 303, 243-246.
16. CONSTANTINOU, A., DAVIES, A.A. and WEST, S.C. (2001). Branch migration and Holliday junction resolution catalyzed by activities from mammalian cells. Cell 104, 259-268.
17. DAVIES, A.A., MASSON, J.Y., MCILWRIATH, M.J., STASIAK, A.Z., STASIAK, A., VENKITARAMAN, A.R. WEST, S.C. (2001). Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol. Cell. 7, 273-282.
18. VAN DYCK, E., STASIAK, A.Z., STASIAK, A. and WEST, S.C. (1999) Binding of double-strand breaks in DNA by human RAD52 protein. Nature, 398, 728-731.
19. BENSON, F.E., BAUMANN, P. and WEST, S.C. (1998) Synergistic actions of RAD51 and RAD52 in recombination and DNA repair. Nature 391, 401-404.
20. EGGLESTON, A.K., MITCHELL, A.H. and WEST, S.C. (1997) In vitro reconstitution of the late steps of genetic recombination in E. coli. Cell, 89, 607-617.
21. BAUMANN, P., BENSON, F. E., and WEST, S. C. (1996). Human RAD51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell, 87, 757-766.
22. PARSONS, C.A., STASIAK, A., BENNETT, R.J., and WEST, S.C. (1995). Structure of a multisubunit complex that promotes DNA branch migration. Nature 374, 375-378.
23. HIOM, K., and WEST, S.C. (1995). The mechanism of branch migration in homologous recombination: Assembly of a RuvAB-Holliday junction complex in vitro. Cell 80, 787-793.
24. SHAH, R., BENNETT, R. J. and WEST, S. C. (1994). Genetic recombination in Escherichia coli: RuvC protein cleaves Holliday junctions at resolution hotspots in vitro. Cell 79, 853-864.
25. BENNETT, R.J. and WEST, S.C. (1993). Cleavage of Holliday junctions by RuvC resolvase: Cleavage specificity and DNA distortion. Cell 74, 1021-1031.
26. TSANEVA, I.R., MÜLLER, B., WEST, S.C. (1992). ATP-dependent branch migration of Holliday junctions promoted by the RuvA and RuvB proteins of E. coli. Cell 69, 1171-1180.
27. DUNDERDALE, H.J., BENSON, F.E., PARSONS, C.A., SHARPLES, G.J., LLOYD, R.G., and WEST, S.C. (1991). The formation and resolution of recombination intermediates by E. coli RecA and RuvC proteins. Nature 354, 506-510.
28. MÜLLER, B., JONES, C., KEMPER, B. and WEST, S.C. (1990). Enzymatic formation and resolution of Holliday structures in vitro. Cell 60, 329-336.
29. CONLEY, E.C. and WEST, S.C. (1989). Homologous pairing and the formation of nascent synaptic intermediates between regions of duplex DNA by RecA protein. Cell 56, 987-995.
30. WEST, S.C. and HOWARD-FLANDERS, P. (1984). Duplex-duplex interactions catalyzed by RecA protein allow strand exchanges to pass double strand breaks in DNA. Cell 37, 683-691.
31. HOWARD-FLANDERS, P., WEST, S.C. and STASIAK, A.J. (1984). Role of RecA spiral filaments in genetic recombination. Nature 309, 215-220.
32. WEST, S.C., COUNTRYMAN, J.K. and HOWARD-FLANDERS, P. (1983). Enzymatic formation of biparental figure-8 molecules from plasmid DNA and their resolution in Escherichia coli. Cell 32, 817-829.
33. WEST, S.C., CASSUTO, E. and HOWARD-FLANDERS, P. (1981). Homologous pairing can occur before DNA strand separation in general genetic recombination. Nature 290, 29-33.
34. WEST, S.C., CASSUTO, E. and HOWARD-FLANDERS, P. (1981). Mechanism of E. coli RecA protein-directed strand exchanges in postreplication repair of DNA. Nature 294, 659-662.