Navigation Links
Evolution of human genome's 'guardian' gives people unique protections from DNA damage
Date:1/16/2008

CINCINNATI Human evolution has created enhancements in key genes connected to the p53 regulatory network the so-called guardian of the genome by creating additional safeguards in human genes to boost the networks ability to guard against DNA damage that could cause cancer or a variety of genetic diseases, an international team of scientists led by Cincinnati Childrens Hospital Medical Center writes in the Jan. 22 Proceedings of the National Academy of Sciences. Because genetically engineered mouse models are increasingly powerful tools in understanding the risks and mechanisms of human diseases and rodents do not have the same evolution-based safeguards in p53 function as humans the study also underscores the need for additional considerations in the interpretation of research using rodent models.

Our findings are especially important because rodents are often used as model organisms to investigate the genetic origins of diseases that affect humans, such as cancer investigators evaluating the impact of DNA-damaging agents, said Anil Jegga, DVM, a researcher in the Division of Biomedical Informatics at Cincinnati Childrens. Rodent models remain important to our understanding of disease processes, although our study suggests the need to address experimentally the differences in p53 regulatory pathways between humans and rodent models.

In the study, Jegga and his colleagues used comparative functional genomics to look systematically at small DNA sequences associated with the promoters, or enhancers, of specific genes that carry out orders from p53. These promoter elements act like antennae responding to activated p53 by boosting target gene expression and function inside a cells nucleus. By comparing these response elements across nearly 50 different binding sites of genes in the p53 network, and looking specifically at genes that repair DNA damage in 14 species (from zebra fish to humans), researchers were able to reveal critical evolutionary changes in their function. The 14 species represented an estimated 500 million years of evolutionary separation, helping investigators determine how the function of p53 response elements was conserved or changed as different species developed. Dr. Jegga said researchers were surprised to find the acquisition of functional response for certain genes involved in DNA metabolism or repair to be mostly unique in humans. While the functional ability of some genes is shared with chimpanzees and rhesus monkeys, researchers said DNA metabolism and repair function it is not shared at all with rodents.

In humans, when DNA damage is detected, the p53 network seems to have gained additional capabilities that allow it to slow cell growth, initiate repairs or, if needed, apoptotic cell death. Apoptotic, or programmed cell death capability in the p53 network, is thought to be evolutionarily conserved throughout the development of vertebrate species and was probably established after the divergence of vertebrates and non-vertebrates. DNA metabolism and repair capabilities controlled by p53 may have emerged more recently in evolutionary history to create primate-specific response characteristics, the researchers explained.

The fact that DNA metabolism and repair genes have undergone this kind of evolution in humans may reflect an increased need for coordinated control of molecular repair activities during DNA replication to allow for the maintenance of genomic integrity during complex differentiation, growth, and aging, said Bruce Aronow, Ph.D., co-director of Computational Medicine at Cincinnati Childrens and a study co-author.

That different strategies to guard our chromosome structures and DNA sequences against damage are subject to evolutionary adaptation is also suggested by other knowledge we have, Dr. Aronow explained. For example, compared to rodents humans have much shorter telomeres, which are regions of highly repetitive DNA at the end of chromosomes that help shield against damage. Shorter telomeres can make people more susceptible to chromosomal damage and increase our risk of developing malignant tumors. When genes replicate, the process does not copy the very ends of the gene, so telomeres act like caps on the ends of shoelaces, helping preserve DNA structure and preventing genetic unraveling and loss of genetic information.

A clue to p53 functional differences may be found in sunlight. Exposure to the ultra-violet rays in sunlight activates the DNA-damage responses of the repair gene (Ddb2) in humans, but the same gene does not function in rodents. Some studies have suggested that rodents may have a reduced need for genetic protection from sunlight because they are nocturnal and have a fur shield.

Although the full implications of these evolutionary points remain far from clear, our work demonstrates that there has been both refinement and evolution of gene networks controlled by p53, Dr. Aronow said. Exciting work is underway by research groups within the National Cancer Institutes Mouse Models of Human Cancer Consortium to develop mice that are genetically engineered to test the combined effects of altering p53 and telomerase, the enzyme that controls the length and stability of repeating DNA sequences in the telomere region. Mouse models will continue to become progressively more powerful tools for studying human cancer and additional information about the p53 network will help us refine our interpretation of pre-clinical research that may lead to improved cancer prevention for at-risk and normal individuals.

In conducting their analysis of p53 target genes, the international research team used comparative DNA sequence analysis and functional tests of highly engineered yeast and mouse cell culture assays to examine 47 established p53 response elements in 14 vertebrate and non-vertebrate species. The study included researchers from the National Institute for Cancer Research (Molecular Mutagenesis Unit, Department of Translational Oncology) in Genoa, Italy, and the Laboratory of Molecular Genetics Chromosome Stability Group of the National Institute of Environmental Health Sciences (National Institutes of Health).


'/>"/>

Contact: Nick Miller
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

Related medicine news :

1. Local Oncology Group Leads Online Effort to Revolutionize Cancer Care
2. Join the Vitamin D Revolution: How to Get 30 Minutes of Daily Sunshine for Optimal Health
3. VIDEO from Medialink and Revolution Health: RevolutionHealth.com Launches Resolutions 2.0
4. UCLA Program Aims to Revolutionize Kidney Transplants
5. Prescription for an electronic revolution?
6. Adapting to pregnancy played key role in human evolution, study shows
7. Evolution Tips the Balance in Moms Favor
8. Informed Medical Communications Sells Consumer Internet Division to Revolution Health
9. Chinas Anti-Aging Revolution
10. New Low-Impact Cosmetic Surgery Treatments Revolutionizing Industry
11. ILC Dover Launches Revolutionary ArmorFlex (R) Pharmaceutical Product Contact Film
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/25/2016)... ... June 25, 2016 , ... Dr. Calvin Johnson ... Recently, he has implemented orthobiologic procedures as a method for treating his patients. ... the first doctors to perform the treatment. Orthobiologics are substances that orthopaedic surgeons ...
(Date:6/24/2016)... ... June 24, 2016 , ... Those who have experienced traumatic events ... turn to unhealthy avenues, such as drug or alcohol abuse, as a coping mechanism. ... tools for healthy coping following a traumatic event. , Trauma sufferers tend to feel ...
(Date:6/24/2016)... MIAMI, Fla. (PRWEB) , ... June 24, 2016 , ... ... Florida Trend magazine’s 2016 Legal Elite. The attorneys chosen by their peers for this ... of Florida. , Seven Greenberg Traurig Shareholders received special honors as members of this ...
(Date:6/24/2016)... , ... June 24, 2016 , ... People across the ... Genome magazine’s Code Talker Award, an essay contest in which patients and their families ... to be presented at the 2016 National Society of Genetic Counselors (NSGC) Annual Education ...
(Date:6/24/2016)... ... 24, 2016 , ... Strategic Capital Partners, LLC (SCP) in ... investment capital for emerging technology companies. SCP has delivered investment events and ... more than a million dollars of capital investment for five companies. ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... Research and Markets has announced the addition of the ... to their offering. ... World Market for Companion Diagnostics covers the world market for ... report includes the following: , World IVD ... (N. America, EU, ROW), 2015-2020 , World IVD Companion ...
(Date:6/24/2016)... 2016  Arkis BioSciences, a leading innovator in ... durable cerebrospinal fluid treatments, today announced it has ... is led by Innova Memphis, followed by Angel ... investors.  Arkis, new financing will accelerate the commercialization ... release of its in-licensed Endexo® technology. ...
(Date:6/23/2016)... 2016 Research and Markets has ... by Type (Organic Chemical (Sugar, Petrochemical, Glycerin), Inorganic Chemical), ... Parenteral) - Global Forecast to 2021" report to ... The global pharmaceutical excipients market is projected to reach ... 6.1% in the forecast period 2016 to 2021. ...
Breaking Medicine Technology: