Penelope Jeggo

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Penelope Jeggo
Born1947 (age 75–76)
Cambridge, England
Alma mater Queen Elizabeth College, University of London
National Institute for Medical Research
Known forDouble-stranded DNA repair
Scientific career
Fields Cell biology
InstitutionsUniversity of Sussex

Penelope "Penny" Jeggo (born September 1947 [1] ) is a noted British molecular biologist, best known for her work in understanding damage to DNA. She is also known for her work with DNA gene mutations. Her interest in DNA damage has inspired her to research radiation biology and radiation therapy and how radiation affects DNA. [2] Jeggo has more than 170 publications that pertain to DNA damage, radiation, and cancer research and has received 3 top science awards/medals for her research. Jeggo has also been a member of several organizations that pertain to radiation biology; these organizations include Committee on Medical Aspects of Radiation in the Environment (COMARE), National Institute for Radiation Science laboratory researcher, and the Multidisciplinary European Low Dose Initiative (MELODI). [2] Jeggo is a member of these organizations, and she is also an editor for several publication journals that are related to cancer and radiation biology. Jeggo is very passionate about her research and in an interview with Fiona Watt claimed that “Although my results contributed only the tiniest smidgeon to scientific knowledge, I gained immense satisfaction from it”. [3]

Contents

Early life and education

Penny Jeggo was born in Cambridge, England. She earned a bachelor's degree in microbiology at Queen Elizabeth College, University of London in 1970. She went on to earn a PhD in genetics at the National Institute for Medical Research (NIMR), London, in the lab of Robin Holliday. [3]

She later held postdoctoral positions with John Cairns, whom she cites as one of her biggest mentors, at the Imperial Cancer Research Fund Mill Hill Laboratory, and with Miroslav Radman at the Université libre de Bruxelles, Belgium. After working for Radman, Jeggo returned in 1980 to Robin Holliday's lab where she began her research on DNA damage and the cells' response to the damage. After more work in Radman's lab, Jeggo, in 1989, moved to the Cell Mutation Unit at Sussex.

When Jeggo reached her thirties, she and her husband started a family giving birth to a son, Matthew. Her husband died from colon cancer shortly after Matthew was born. The death of Matthew's father almost discouraged her from continuing her research in cancer and radiation biology. She returned to her research and further researched cancer and DNA a few years after her husband's death. [3]

Career and legacy

Jeggo's primary legacy is her work on DNA damage responses and DNA repair of double strand breaks. [4] Much of her early work involved Chinese hamster ovary cells, a commonly studied cell line also known as CHO. Using standard techniques of microbial genetics, she tested more than 9,000 colonies before isolating six X-ray-sensitive mutants. This was the first step in understanding the mechanisms involved in the repair of X-irradiation-induced DNA damage. [5]

Jeggo is particularly well known for identifying two components of an enzyme called DNA-dependent protein kinase (DNA-PK) as being important in DNA non-homologous end joining (NHEJ), a pathway by which mammalian cells repair themselves. This discovery was a major breakthrough in understanding the double strand break repair pathway in mammals. In addition, Jeggo showed that NHEJ is important for the development of the immune response. [4] She also studied LIG4-mutant mice and how exposure to oxygen increases the number of double-stranded breaks due to the failure to repair DNA breaks. [6]

Positions and events

Penelope Jeggo has participated in various symposiums and conventions where she has discussed her research and given talks on cell biology in relation to radiation biology. In 2001, Jeggo became a founding member of the Genome Damage and Stability Center, a research center established at the University of Sussex. [3] In 2002, Jeggo was a lecturer for the 6th Cancer/Genome Priority Seminar at the Nagasaki University. She discussed the importance of low-dose radiation and molecular cell biology. [7] In 2003, Jeggo was given the title of Professorial Fellow of the University Sussex. She also attended the 2003 Gordon Research Conference on Genetic Toxicology as the conference chair. [8]

In 2012, Jeggo was elected into the Academy of Medical Science Fellows along with 46 other British researchers for their dedication to research and for their contributions to the medical sciences. [9] In 2014, she was the chair of the Scientific Advisory Board for the Ataxia-Telangiectasia Society. [10] She was an invited speakers for the symposium on DNA damage response to radiation in 2015 at the International Congress of Radiation Research (ICRR). [11]

Jeggo was scheduled to represent the United Kingdom as one of the keynote speakers at the World Congress on Medical Physics and Biomedical Engineering in Prague 2018. [12]

Awards

Jeggo has won the 2011 Penelope Jeggo Bacq and Alexander Award for her research with radiation biology and cancer. [13] She was also the 2013 recipient of the United Kingdom Genome Stability Network medal for her research in DNA damage of the cell. [14] Penelope Jeggo won her third award in 2013 for the Silvanus Thompson Medal from the British Institute of Radiology. Her third award was also for her research in radiation and DNA damage. [15]

Other research and publications

One of Jeggo's first publication was on her research with double stranded DNA break repair mutants and the effect it has on V(D)J recombination. She and her fellow researchers discovered that two mutants, xrs-6 and XR-1, play a role in restoring V(D)J recombination and were able to identify which genes are affected by DNA breakage. [16]

In one publication, Jeggo worked with other researchers on the Ataxia telangiectasia and Rad3 related protein (ATR) and how mutation in ATR can damage DNA which consequently prevents cilia signaling. [17] The team used zebrafish as a model organism in order to test the protein defect and its effects on cilia. Jeggo had researched this subject previously in 2003 when she and fellow scientists concluded that when ATR is exposed to UV radiation, caused a splice mutation in DNA which led to Seckel syndrome, a disorder that retards growth while the fetus develops in the uterus. [18]

To continue her research on DNA damage, Jeggo studied aging and stem cells. She found that the inability of DNA Ligase IV to repair breaks in stem cell DNA contributes to the aging of our cells. Jeggo and her team found that breaks in the stem cell DNA come from genetics as well as environmental stress which inhibits the lifespan of stem cells and therefore contributes to aging. [19]

Jeggo began researching epigenetic changes and the effects that epigenetics have on DNA repair. She found that a mutation in ataxia telangiectasia mutated kinase (ATM) causes damage to DNA and chromatin structure. Jeggo's review showed that nucleosomes are important in DNA repair. However, she claims that more research on the changes in chromatin structure is necessary to further understanding of DNA damage and repair mechanisms. [20]

Related Research Articles

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encodes its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

<span class="mw-page-title-main">Ataxia–telangiectasia</span> Rare, neurodegenerative, autosomal recessive human disease causing severe disability

Ataxia–telangiectasia, also referred to as ataxia–telangiectasia syndrome or Louis–Bar syndrome, is a rare, neurodegenerative, autosomal recessive disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease. A–T affects many parts of the body:

<span class="mw-page-title-main">ATM serine/threonine kinase</span>

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

<span class="mw-page-title-main">Mutant</span> Phenotypically-different organism resulting from a mutation

In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It is a characteristic that would not be observed naturally in a specimen. The term mutant is also applied to a virus with an alteration in its nucleotide sequence whose genome is in the nuclear genome. The natural occurrence of genetic mutations is integral to the process of evolution. The study of mutants is an integral part of biology; by understanding the effect that a mutation in a gene has, it is possible to establish the normal function of that gene.

<span class="mw-page-title-main">Ataxia telangiectasia and Rad3 related</span> Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR, also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1), is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

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

Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.

<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">Evelyn M. Witkin</span> American geneticist (1921–2023)

Evelyn M. Witkin was an American bacterial geneticist at Cold Spring Harbor Laboratory (1944–1955), SUNY Downstate Medical Center (1955–1971), and Rutgers University (1971–1991). Witkin was considered innovative and inspirational as a scientist, teacher and mentor.

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

DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase consisting of a single polypeptide chain of 4,128 amino acids.

<span class="mw-page-title-main">LIG4</span> Protein-coding gene in the species Homo sapiens

DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene.

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

Artemis is a protein that in humans is encoded by the DCLRE1C gene.

<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">TOPBP1</span> Protein-coding gene in the species Homo sapiens

DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the TOPBP1 gene.

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

Probable helicase senataxin is an enzyme that in humans is encoded by the SETX 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.

The MRN complex is a protein complex consisting of Mre11, Rad50 and Nbs1. In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

References

  1. ↑ "Prof Penelope Ann Jeggo, director at The Ataxia-telangiectasia Society, Harpenden". www.directorstats.co.uk. Retrieved 21 November 2017.
  2. 1 2 "EUROPEAN RADIATION RESEARCH SOCIETY". www.errs.eu. Retrieved 21 November 2017.
  3. 1 2 3 4 Watt, Fiona M. (1 November 2004). "Penelope Jeggo". Journal of Cell Science. 117 (23): 5459–5460. doi:10.1242/jcs.01509. PMID   15509862. S2CID   219207440 . Retrieved 23 March 2014.
  4. 1 2 "Dr. Penny Jeggo : University of Sussex" . Retrieved 23 March 2014.
  5. ↑ Jeggo, PA; LP Kemp (December 1983). "X-ray-sensitive mutants of Chinese hamster ovary cell line. Isolation and cross-sensitivity to other DNA-damaging agents". Mutation Research. 112 (6): 313–327. doi:10.1016/0167-8817(83)90026-3. PMID   6197643.
  6. ↑ Nijnik, Anastasia; et al. (7 June 2007). "DNA repair is limiting for haematopoietic stem cells during ageing". Nature. 447 (7145): 686–690. Bibcode:2007Natur.447..686N. doi:10.1038/nature05875. PMID   17554302. S2CID   4332976.
  7. ↑ "NRGIC: Nagasaki University Research Centre for Genomic Instability and Carcinogenesis". www.nrgic.prj.nagasaki-u.ac.jp. Retrieved 21 November 2017.
  8. ↑ Jeggo, Project Director Penelope (15 February 2003). "Gordon Research Conference on Genetic Toxicology".{{cite journal}}: Cite journal requires |journal= (help)
  9. ↑ "Academy of Medical Sciences - September 2011 - Newsletter". www.acmedsci-updates.org.uk. Retrieved 21 November 2017.
  10. ↑ "The Ataxia-Telangiectasia Society Annual Report and Accounts" (PDF). 2014.
  11. ↑ "Information for ICRR2015". Journal of Radiation Research. 57 (Suppl 1): i127–i141. 2016. Bibcode:2016JRadR..57I.127.. doi:10.1093/jrr/rrw050. ISSN   0449-3060. PMC   4990118 . PMID   27538843.
  12. ↑ "IUPESM 2018 - Keynote Speakers". www.iupesm2018.org. Retrieved 21 November 2017.
  13. ↑ "EUROPEAN RADIATION RESEARCH SOCIETY". www.errs.eu. Retrieved 21 November 2017.
  14. ↑ "News & Events". www.genomestabilitynetwork.org.uk. Retrieved 21 November 2017.
  15. ↑ "Sussex molecular biologist wins Silvanus Thompson Medal : 3 May 2013 : ... : Bulletin : University of Sussex". www.sussex.ac.uk. mi79. Retrieved 21 November 2017.{{cite web}}: CS1 maint: others (link)
  16. ↑ "Impairment of V(D)J recombination in double-strand break rep". Science. Washington. 260 (5105): 207. 9 April 1993. ProQuest   213570381.
  17. ↑ Stiff, Tom; Tena, Teresa Casar; O'Driscoll, Mark; Jeggo, Penny A.; Philipp, Melanie (15 April 2016). "ATR promotes cilia signalling: links to developmental impacts". Human Molecular Genetics. 25 (8): 1574–1587. doi:10.1093/hmg/ddw034. ISSN   0964-6906. PMC   4805311 . PMID   26908596.
  18. ↑ O'Driscoll, Mark; Ruiz-Perez, Victor L.; Woods, C. Geoffrey; Jeggo, Penny A.; Goodship, Judith A. (17 March 2003). "A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome". Nature Genetics. 33 (4): 497–501. doi: 10.1038/ng1129 . ISSN   1546-1718. PMID   12640452.
  19. ↑ Nijnik, Anastasia; Woodbine, Lisa; Marchetti, Caterina; Dawson, Sara; Lambe, Teresa; Liu, Cong; Rodrigues, Neil P.; Crockford, Tanya L.; Cabuy, Erik (7 June 2007). "DNA repair is limiting for haematopoietic stem cells during ageing". Nature. 447 (7145): 686–690. Bibcode:2007Natur.447..686N. doi:10.1038/nature05875. ISSN   1476-4687. PMID   17554302. S2CID   4332976.
  20. ↑ Jeggo, Penny A.; Downs, Jessica A.; Gasser, Susan M. (5 October 2017). "Chromatin modifiers and remodellers in DNA repair and signalling". Philosophical Transactions of the Royal Society B: Biological Sciences. 372 (1731): 20160279. doi:10.1098/rstb.2016.0279. ISSN   0962-8436. PMC   5577457 . PMID   28847816.
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