Simon Boulton

Last updated

Simon Boulton
Born
Simon Joseph Boulton
Alma mater
Awards
Scientific career
Institutions
Thesis The functional characterisation of Ku in the budding yeast, Saccharomyces cerevisiae  (1998)
Website www.london-research-institute.org.uk/research/simon-boulton

Simon Joseph Boulton FRS is a British scientist who has made important contributions to the understanding of DNA repair and the treatment of cancer resulting from DNA damage. He currently occupies the position of Senior Scientist and group leader of the DSB Repair Metabolism Laboratory at the Francis Crick Institute, London. He is also an honorary Professor at University College London. [4] [5] [6] [7]

Contents

Early life and education

Boulton studied Molecular Biology at the University of Edinburgh, then studied for a Ph.D. at the University of Cambridge under Professor Steve Jackson of the Gurdon Institute from 1994 to 1998. [8] It was at Cambridge that Boulton began researching mechanisms of DNA. He has described his first exposure to the research environment at Cambridge as "extremely influential." [3] [9] [10]

Research

The website of Cancer Research UK explains Boulton's work in this way: human DNA "is constantly under assault from chemical reactions taking place in our bodies and from things we're exposed to in our everyday lives....Most of the time, DNA damage is repaired successfully by the cell. But if the cell continues to grow whilst its DNA is already damaged, it can lead to cancer." Boulton is learning about DNA damage repair "by first studying it inside a microscopic worm called C. elegans and then extending these findings to human cells," an approach that has revealed "remarkable similarities between the genes and proteins used to repair DNA damage in the worm and in humans....By studying this fundamental process of DNA damage repair, the researchers have contributed to our understanding of how faults in the system can lead to cancer." [11]

Boulton himself has explained his work at the DNA Damage Response Laboratory as follows: "DNA is a highly reactive molecule that is susceptible to damage. Fortunately, cells have evolved specialised repair processes that are remarkably efficient in correcting specific types of DNA damage. Failure to correctly repair DNA damage will lead to mutagenic change, which can contribute to ageing and cancer. Indeed, defects in genes that repair DNA damage are the underlying cause of a number of hereditary ageing/cancer predisposition syndromes such as Fanconi anemia and Blooms. The focus of my lab is to identify new DNA repair genes, understand how they work in DNA repair in mitotic and meiotic cells and determine how defects in these processes contribute to human disease such as cancer. We hope that our work will provide an improved understanding of how DNA repair works and how, when DNA repair is compromised, it contributes to cancer/ageing and or infertility disorders in humans." [12] According to the Royal Society, Boulton's research has resulted in several major breakthroughs in understanding; these are viewed as highly promising with regard to the potential development of new cancer treatments. [13]

DNA Damage Response Laboratory

DNA damage, due to environmental factors and normal metabolic processes inside the cell. A special enzyme, DNA ligase (shown here in color), encircles the double helix to repair a broken strand of DNA. DNA ligase is responsible for repairing the millions of DNA breaks generated during the normal course of a cell's life. Without molecules that can mend such breaks, cells can malfunction, die, or become cancerous. DNA Repair.jpg
DNA damage, due to environmental factors and normal metabolic processes inside the cell. A special enzyme, DNA ligase (shown here in color), encircles the double helix to repair a broken strand of DNA. DNA ligase is responsible for repairing the millions of DNA breaks generated during the normal course of a cell's life. Without molecules that can mend such breaks, cells can malfunction, die, or become cancerous.

DNA is highly reactive and susceptible to damage from things we are exposed to in everyday life. Fortunately, DNA has evolved processes in which it has the ability to repair itself. [14] If the damages are not repaired and it continues to grow, mutagenic changes occur causing ageing and cancer. Boulton is responsible for identifying these new DNA repair genes, understanding how these genes work in DNA, and determining how the defects in these processes contribute to human diseases. [14] To fulfil these tasks, Boulton studies the DNA damage repair inside a specific worm called C. elegans, then extends these findings to human cells. Through this process, he has found "remarkable similarities between the genes and proteins used to repair DNA damage in the worm and in humans....By studying this fundamental process of DNA damage repair, the researchers have contributed to our understanding of how faults in the system can lead to cancer." [15] Boulton's research has resulted in several major breakthroughs that are viewed as highly promising with regard to the potential development of new cancer treatments. [1]

Boulton's papers about his work have appeared in a number of major scientific journals, such as Nature , [16] [17] Science , [18] Cell , [19] [20] [21] and Molecular Cell . [14] [22]

Career

After receiving his Ph.D. from Cambridge, Boulton completed postdoctoral fellowships funded by the European Molecular Biology Organization and the Human Frontier Science Program at Harvard Medical School. He first worked under Professor Nicholas Dyson of the Massachusetts General Hospital Cancer Center, then under Professor Marc Vidal of the Dana Faber Cancer Institute at Harvard Medical School. [8] In 2002, Boulton joined Cancer Research UK, working at its London Research Institute, Clare Hall Laboratories, in South Mimms, and in Hertfordshire. He established his own research group there, and was eventually promoted to Senior Scientist in 2007. [23] He is a member of the Editorial Board for Genes & Development . [24]

Boulton’s PhD supervisor, Stephen P. Jackson, has said that it is Boulton's distinctive combination of approaches that has allowed Boulton to make seminal contributions to DNA repair, genome instability, and cancer. [3] Among Boulton's achievements is the discovery that the gene RTEL1 serves as an anti-recombinase that affects genome stability and cancer and counteracts toxic recombination. In addition, he and his team discovered the PBZ motif and determined that ALC1 (Amplified in Liver Cancer 1) is a poly(ADP-ribose)-activated chromatin-remodelling enzyme required for DNA repair, and that poly (ADP-ribosyl)ation (PAR) is a post-translational modification of proteins that play an important role in mediating protein interactions and the recruitment of specific protein targets. [3]

Also, he has discovered that the Fanconi Anemia proteins FANCM and FAAP24 are required for checkpoint-kinase signalling (ATR) in response to DNA damage and established that DNA repair defects of Fanconi Anemia cells can be suppressed by blocking non-homologous end joining. [3] He has also demonstrated that a newly identified helicase, RTEL1, plays a crucial role in repairing double-stranded DNA breaks by means of homologous recombination (HR) – a discovery that has great therapeutic significance and that has already led to the development of treatments, with a drug currently undergoing clinical tests. [25] [26]

The discoveries made in Boulton's laboratory have led to new therapeutic approaches. The findings about ALC1 may prove to have significant implications for the treatment of liver cancer. The discoveries about Fanconi Anemia proteins, moreover, suggest that NHEJ inhibitors might help suppress Fanconi Anemia patients' predisposition to cancer. [3]

Honours and awards

Boulton won the Colworth Medal [2] from the Biochemical Society in 2006, [3] and was selected to give the EACR Young Cancer Researcher of the Year award lecture in 2008. He was presented with the Eppendorf/Nature Young Investigator Award in 2008 for his research into DNA damage, specifically his work with RTEL1. [25] He became a member of the European Molecular Biology Organization (EMBO) in 2009, and was awarded a Royal Society Wolfson Research Merit Award in 2010. He won the EMBO Gold Medal in 2011 for his research on DNA repair mechanisms. The election committee said that it was "particularly impressed by his pioneering role in establishing the nematode worm, C. elegans, as a model system to study genome instability." [3] In 2011, Boulton was chosen to give the Royal Society Francis Crick Prize Lecture, an honour awarded annually by the Royal Society. [27] He was selected for this honour in recognition of his achievements in the field of DNA repair. [23] Boulton was elected as a Fellow of the Academy of Medical Sciences in 2012. [28] In 2013, Boulton was the recipient of the Paul Marks Prize for Cancer Research, which recognises a new generation of leaders in cancer research who are making significant contributions to the understanding of cancer. [29] [30] He was elected a Fellow of the Royal Society in May 2022. [31]

Related Research Articles

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are human genes and their protein products, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Non-homologous end joining</span> Pathway that repairs double-strand breaks in DNA

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.

<span class="mw-page-title-main">Ku70</span> Protein-coding gene in the species Homo sapiens

Ku70 is a protein that, in humans, is encoded by the XRCC6 gene.

<span class="mw-page-title-main">Fanconi anemia, complementation group C</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group C protein is a protein that in humans is encoded by the FANCC gene. This protein delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. Mutations in this gene result in Fanconi anemia, a human rare disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages.

<span class="mw-page-title-main">FANCA</span> Protein-coding gene in the species Homo sapiens

Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.

<span class="mw-page-title-main">FANCD2</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN and FANCO.

<span class="mw-page-title-main">FANCG</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.

<span class="mw-page-title-main">ERCC4</span> Protein-coding gene in the species Homo sapiens

ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

<span class="mw-page-title-main">FANCF</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.

<span class="mw-page-title-main">FANCE</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the FANCE gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA cross-linking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation groufcrp E.

<span class="mw-page-title-main">FANCL</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

<span class="mw-page-title-main">PALB2</span> Protein-coding gene in the species Homo sapiens

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

<span class="mw-page-title-main">FANCM</span> Mammalian protein found in Homo sapiens

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.

FANC proteins are a network of at least 15 proteins that are associated with a cell process known as the Fanconi anemia.

Simon N. Powell is a British cancer researcher and radiation oncologist residing in New York City.

<span class="mw-page-title-main">Ketan J. Patel</span>

Ketan Jayakrishna Patel is a British–Kenyan scientist who is Director of the MRC Weatherall Institute of Molecular Medicine and the MRC Molecular Haematology Unit at the University of Oxford. Until 2020 he was a tenured principal investigator at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB).

Agata Smogorzewska is a Polish-born scientist. She is an associate professor at Rockefeller University, heading the Laboratory of Genome Maintenance. Her work primarily focuses on DNA interstrand crosslink repair and the diseases resulting from deficiencies in this repair pathway, including Fanconi anemia and karyomegalic interstitial nephritis.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

  1. 1 2 "Repairing the Code". The Royal Society. Retrieved 24 May 2013.
  2. 1 2 Boulton, S. J. (2006). "Cellular functions of the BRCA tumour-suppressor proteins". Biochemical Society Transactions. 34 (Pt 5): 633–45. doi:10.1042/BST0340633. PMID   17052168.
  3. 1 2 3 4 5 6 7 8 "April 2011". The Medical Blog. Retrieved 24 May 2013.
  4. ↑ Simon Boulton's publications indexed by the Scopus bibliographic database. (subscription required)
  5. ↑ Boulton, S. J.; Jackson, S. P. (1998). "Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing". The EMBO Journal. 17 (6): 1819–1828. doi:10.1093/emboj/17.6.1819. PMC   1170529 . PMID   9501103.
  6. ↑ Boulton, S.; Jackson, S. P. (1996). "Identification of a Saccharomyces cerevisiae Ku80 homologue: Roles in DNA double strand break rejoining and in telomeric maintenance". Nucleic Acids Research. 24 (23): 4639–4648. doi:10.1093/nar/24.23.4639. PMC   146307 . PMID   8972848.
  7. ↑ Boulton, S. J.; Jackson, S. P. (1996). "Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways". The EMBO Journal. 15 (18): 5093–5103. doi:10.1002/j.1460-2075.1996.tb00890.x. PMC   452249 . PMID   8890183.
  8. 1 2 Boulton, Simon. "Keynote Seminar "Biologie & Clinique"" (PDF). Institut Paoli-Calmettes. Retrieved 24 May 2013.
  9. ↑ "Keynote Speakers" (PDF). institutpaolicalmettes.
  10. ↑ "EMBO gold medal 2011 awarded to Simon Boulton". EMBO.
  11. ↑ "Understanding how cells repair DNA damage". Cancer Research UK.
  12. ↑ "Simon Boulton : DNA Damage Response". London Research Institute. Archived from the original on 4 August 2014.
  13. ↑ "The Royal Society". Repairing the Code.
  14. 1 2 3 "Simon Boulton". London-Research Institute. Archived from the original on 4 August 2014.
  15. ↑ "Simon Boulton". Cancer Research UK. Retrieved 24 May 2013.
  16. ↑ Boulton, S. J. (2009). "DNA repair: A heavyweight joins the fray". Nature. 462 (7275): 857–858. Bibcode:2009Natur.462..857B. doi: 10.1038/462857a . PMID   20016586. S2CID   4373844.
  17. ↑ Boulton, S. J. (2010). "DNA repair: Decision at the break point". Nature. 465 (7296): 301–302. Bibcode:2010Natur.465..301B. doi:10.1038/465301a. PMID   20485424. S2CID   4387088.
  18. ↑ Ahel, D.; Horejsí, Z.; Wiechens, N.; Polo, S. E.; Garcia-Wilson, E.; Ahel, I.; Flynn, H.; Skehel, M.; West, S. C.; Jackson, S. P.; Owen-Hughes, T.; Boulton, S. J. (2009). "Poly(ADP-ribose)-Dependent Regulation of DNA Repair by the Chromatin Remodeling Enzyme ALC1". Science. 325 (5945): 1240–1243. Bibcode:2009Sci...325.1240A. doi:10.1126/science.1177321. PMC   3443743 . PMID   19661379.
  19. ↑ Vannier, J. B.; Pavicic-Kaltenbrunner, V; Petalcorin, M. I.; Ding, H; Boulton, S. J. (2012). "RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity". Cell. 149 (4): 795–806. doi: 10.1016/j.cell.2012.03.030 . PMID   22579284.
  20. ↑ Boulton, S. J. (2009). "Condensin(g) crossover control to a few breaks". Cell. 139 (1): 21–3. doi: 10.1016/j.cell.2009.09.016 . PMID   19804748. S2CID   15262949.
  21. ↑ Barber, L. J.; Youds, J. L.; Ward, J. D.; McIlwraith, M. J.; O'Neil, N. J.; Petalcorin, M. I.; Martin, J. S.; Collis, S. J.; Cantor, S. B.; Auclair, M; Tissenbaum, H; West, S. C.; Rose, A. M.; Boulton, S. J. (2008). "RTEL1 maintains genomic stability by suppressing homologous recombination". Cell. 135 (2): 261–71. doi:10.1016/j.cell.2008.08.016. PMC   3726190 . PMID   18957201.
  22. ↑ Chapman, J. R.; Taylor, M. R. G.; Boulton, S. J. (2012). "Playing the End Game: DNA Double-Strand Break Repair Pathway Choice". Molecular Cell. 47 (4): 497–510. doi: 10.1016/j.molcel.2012.07.029 . PMID   22920291.
  23. 1 2 "HFSP Alumni News: Simon Boulton awarded the 2011 Francis Crick Lecture". Human Frontier Science Program. Retrieved 24 May 2013.
  24. ↑ "Genes & Development -- Genes & Development Editorial Board".
  25. 1 2 "Dr Simon Boulton receives the 2008 Eppendorf Young European Investigator Award". Pro Health Service Zone. Retrieved 24 May 2013.
  26. ↑ "Dr Simon Boulton receives the 2008 Eppendorf Young European Investigator Award". Pro Health Service Zone.
  27. ↑ "Repairing the code". The Royal Society. 7 December 2011.
  28. ↑ "Welcome to the Academy of Medical Sciences". Academy of Medical Sciences.
  29. ↑ "Paul Marks Prize for Cancer Research". Memorial Sloan Kettering Cancer Center.
  30. ↑ "Doing the twist on damaged DNA – Simon Boulton wins the Paul Marks cancer research prize". Cancer Research UK. 23 September 2013.
  31. ↑ "Outstanding scientists elected as Fellows and Foreign Members of the Royal Society". Royal Society. 10 May 2022. Retrieved 11 May 2022.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.