Albert J. Fornace Jr.

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Albert J. Fornace Jr. (born 1949) is a professor in the departments of Oncology, Biochemistry and Molecular & Cellular Biology, and Radiation Medicine at Georgetown University. He has also been awarded the Molecular Cancer Research Chair at Lombardi Comprehensive Cancer Center, joining Georgetown in 2006 from the Harvard School of Public Health. Earlier, he was chief of the Gene Response Section at the National Cancer Institute. He graduated from La Salle College High School in Philadelphia, Pennsylvania (1967), and received his B.S. (1970) and M.D. (1972) from the Jefferson-Penn State joint pre-medical/medical program.

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Research career

Fornace has made a variety of notable discoveries in the fields of cancer research, molecular biology, radiation biology, and toxicology with particular emphasis on understanding stress-signaling mechanisms in both normal and cancer cells. This has focused on understanding how cells and organisms respond to genotoxic (DNA damaging) agents, such as radiation, that can cause cancer – as well as being used for its treatment. He was one of the first to show that human and other mammalian cells can respond at the gene level to genotoxic stress, and isolated many of the first known DNA-damage-inducible genes. [1] This included the GADD45A gene [2] and other members of the GADD (growth-arrest and DNA-damage inducible) group. [3]

His laboratory went on to show that many of these genes have roles in growth control, [4] DNA repair, [5] and resistance to cancer, [6] and he has had made important contributions in the characterization of pathways (such as TP53) involved in these critical cellular processes. [7] He has been a pioneer in the use of genomic and metabolomic approaches to understand system-wide effects of damaging agents like radiation. [8] [9] In the case of metabolomics, Fornace is the founding director of the Waters Center of Innovation at Georgetown University in 2011, and the Center for Metabolomic Studies at Georgetown University Medical Center in 2019.

Many of Fornace's studies have used ionizing and UV radiation as model stress agents. These studies also have practical implications for health risks of radiation, assessment of radiation injury, as well as cancer treatment. Since 2010, he has directed a NASA Specialized Center of Research to assess cancer risk during long-term space missions. [10] [11]

Earlier studies focused on DNA repair and DNA recombination. Using sensitive DNA strand break assays in human cells, he was the first to show scission events by nucleotide excision repair, [12] as well as recombination of chromosomal DNA containing damaged DNA. [13] While in Dr. Jerry Crabtree’s laboratory, he elucidated a type of common regional genetic duplication event that occurs over an evolutionary time scale in humans. [14]

Fornace has more than 410 publications with over 52,000 citations (Google Scholar). He has mentored many research fellows and students who have gone on to successful scientific careers. [15] While at the NIH he received a variety of awards including the Public Health Service Outstanding Service Medal. At Georgetown University he received the Medical Center Leadership in Research Award. In the radiation field he has received multiple awards including the Radiation Research Society Excellence in Mentoring Award as well as the Failla Award of the Radiation Research Society, which is the annual career award to an outstanding member of the radiation research community in recognition of a history of major contributions to the field. In 2020, he was elected a Fellow in the National Academy of Inventors (NAI).

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.

Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic substances are not mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.

<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 encode 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">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. 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">Natural competence</span> Ability of cells to alter their own genetics by taking up extracellular DNA

In microbiology, genetics, cell biology, and molecular biology, competence is the ability of a cell to alter its genetics by taking up extracellular ("naked") DNA from its environment in the process called transformation. Competence may be differentiated between natural competence, a genetically specified ability of bacteria which is thought to occur under natural conditions as well as in the laboratory, and induced or artificial competence, which arises when cells in laboratory cultures are treated to make them transiently permeable to DNA. Competence allows for rapid adaptation and DNA repair of the cell. This article primarily deals with natural competence in bacteria, although information about artificial competence is also provided.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive genes in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive genes. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

<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.

Postreplication repair is the repair of damage to the DNA that takes place after replication.

The Growth Arrest and DNA Damage or gadd45 genes, including GADD45A GADD45B, and GADD45G, are implicated as stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation. Gadd45 proteins interact with other proteins implicated in stress responses, including PCNA, p21, Cdc2/CyclinB1, MEKK4, and p38 kinase.

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">RAD17</span> Protein-coding gene in the species Homo sapiens

Cell cycle checkpoint protein RAD17 is a protein that in humans is encoded by the RAD17 gene.

<span class="mw-page-title-main">GADD45A</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.

<span class="mw-page-title-main">RAD52</span> Protein-coding gene in the species Homo sapiens

RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 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">GADD45B</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible, beta, also known as GADD45B, is a protein which in humans is encoded by the GADD45B gene.

<span class="mw-page-title-main">PPP1R15A</span> Protein found in humans

Protein phosphatase 1 regulatory subunit 15A also known as growth arrest and DNA damage-inducible protein GADD34 is a protein that in humans is encoded by the PPP1R15A gene.

<span class="mw-page-title-main">GADD45G</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer.

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.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

Bernd Kaina, born on 7 January 1950 in Drewitz, is a German biologist and toxicologist. His research is devoted to DNA damage and repair, DNA damage response, genotoxic signaling and cell death induced by carcinogenic DNA damaging insults.

References

  1. ↑ Fornace, A. J., Jr, Alamo, I. J., and Hollander, M. C. DNA damage-inducible transcripts in mammalian cells. Proc Natl Acad Sci U S A 85: 8800-8804, 1988.
  2. ↑ Liebermann, D. A., & Hoffman, B. (2013). Gadd45 stress sensor genes. New York: Springer. ISBN   978-1-4614-8289-5
  3. ↑ Fornace, A. J., Jr, Nebert, D. W., Hollander, M. C., Luethy, J. D., Papathanasiou, M., Fargnoli, J., and Holbrook, N. J. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol 9: 4196-4203, 1989.
  4. ↑ Bulavin, D. V., Higashimoto, Y., Popoff, I. J., Gaarde, W. A., Basrur, V., Potapova, O., Appella, E., and Fornace, A. J., Jr. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411: 102-107, 2001.
  5. ↑ Smith, M. L., Chen, I. T., Zhan, Q., Bae, I., Chen, C. Y., Gilmer, T. M., Kastan, M. B., O’Connor, P. M., and Fornace, A. J., Jr. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266: 1376-1380, 1994.
  6. ↑ Kastan, M. B., Zhan, Q., el-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., and Fornace, A. J., Jr. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587-597, 1992.
  7. ↑ Fornace, A. J., Jr. Mammalian genes induced by radiation; activation of genes associated with growth control. Annual Rev. Genetics 26: 507-526, 1992.
  8. ↑ Amundson, S. A., Bittner, M., Chen, Y., Trent, J., Meltzer, P., and Fornace, A. J., Jr. Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses. Oncogene 18: 3666-3672, 1999.
  9. ↑ Coy, S. L., Cheema, A. K., Tyburski, J. B., Laiakis, E. C., Collins, S. P., and Fornace, A. J., jr. Radiation metabolomics and its potential in biodosimetry. Int J Radiat Biol 87: 802-823, 2011.
  10. ↑ Datta, K., Suman, S., Kallakury, B. V., and Fornace, A. J., Jr. Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS One 7: e42224, 2012.
  11. ↑ Mironova, N. Cancer and spaceflight. Aerospace America, 30-35, 2014
  12. ↑ Fornace, A. J., Jr, Kohn, K. W., and Kann, H. E. J. DNA single-strand breaks during repair of UV damage in human fibroblasts and abnormalities of repair in xeroderma pigmentosum. Proc Natl Acad Sci U S A 73: 39-43, 1976.
  13. ↑ Fornace, A. J., Jr. Recombination of parent and daughter strand DNA after UV-irradiation in mammalian cells. Nature 304: 552-554, 1983.
  14. ↑ Fornace, A. J., Jr, Cummings, D. E., Comeau, C. M., Kant, J. A., and Crabtree, G. R. Single-copy inverted repeats associated with regional genetic duplications in gamma fibrinogen and immunoglobulin genes. Science 224: 161-164, 1984.
  15. ↑ Professor Albert J. Fornace Jr. Laboratory: "People". Retrieved July 14, 2017.
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