Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

When the "guardian" and the "caretaker" of the genome join forces

26.01.2018

Scientists from Konstanz, Ulm and Karlsruhe decipher a biochemical mechanism significant for tumour biology

Achievement in the field of cancer research: Biologists and chemists at the University of Konstanz decipher a molecular mechanism of the cell with relevance for the development of cancer and the fight against that disease. Particularly important is the interaction between the tumour-suppressor protein p53, known as the "guardian of the genome", and the enzyme PARP-1, the "caretaker of the genome".


A molecular mechanism deciphered: Once activated, e.g. through DNA damage, the enzyme PARP-1 forms the biopolymer PAR (poly(ADP-ribose)). PAR, in turn, initiates binding to the tumour-suppressor protein p53 in the region of the C-terminal domain (CTD). PARP-1 will then modify p53 with the PAR biopolymer. As depicted in the lower part of the picture, these molecular processes have far-reaching implications for a number of biochemical and cellular functions that play an important role in tumour biology.

Picture: Aswin Mangerich, University of Konstanz

The research project was carried out in collaboration with the University of Ulm and the Karlsruhe Institute of Technology (KIT), and the findings were published in the prestigious scientific journal Nucleic Acids Research (NAR) on 25 January 2018.

Every single day, internal and external influences such as metabolic processes, inflammatory reactions, environmental toxins and radiation cause thousands of random damages to the genetic material (DNA) of every cell of the human body. If the cell cannot "repair" these DNA damages in time, mutations and the development of cancer might be the result.

Normally, if a cell is at risk of turning into a cancer cell, the protein p53 will be activated. p53 triggers several molecular processes that bring cell division to a stop ("cell cycle arrest") and improve the accuracy of DNA repair.

"Through this arrest, the cell gains time to repair dangerous DNA damage or, if there is an overwhelming load of damage, triggers programmed cell death ('apoptosis')”, says toxicologist and biochemist Dr. Aswin Mangerich, who heads the project at Professor Alexander Bürkle's Chair of Molecular Toxicology at the University of Konstanz. "In this way, p53 counteracts the development of cancer and is therefore also known as the 'guardian of the genome'", says Mangerich.

The protein p53 is highly relevant for biomedicine: In one half of all human tumour types, the p53 gene is mutated (irreversibly changed), whereby its cancer-combating function is suppressed. These mutations give the cancer cells a survival advantage, since the important defence mechanisms of DNA repair and programmed cell death are turned off.

The scientists from Konstanz have now deciphered the molecular mechanism how the biochemical and cellular functions of p53 in interaction with the enzyme PARP-1 are controlled. "PARP-1 helps to coordinate DNA repair processes in the cell, and this is why it has been nicknamed the 'caretaker of the genome'", says Aswin Mangerich. Dr. Arthur Fischbach, who is the lead author of the paper and worked on the project during his doctoral thesis, adds:

"The enzyme PARP-1 detects DNA damage, is activated and forms the biopolymer poly(ADP-ribose) as one of the first reactions of the cell. In our paper we report the discovery that p53 first has to engage in a non-covalent (loose) binding to existing biopolymer. Only then, in a second step, can covalently (firmly) attached biopolymer be produced right on the p53 protein. This modification of p53 has far-reaching implications for the regulation of biochemical and cellular functions of p53." The 'guardian' and the 'caretaker' of the genome join forces in case of danger to a cell, with the caretaker calling in the guardian and telling him what to do.

Financial support for the research project was provided by the German Research Foundation (DFG), the Collaborative Research Center 969 (SFB 969), as well as the Research School Chemical Biology and the Zukunftskolleg of the University of Konstanz, which are funded in the context of the German Excellence Initiative.

Original publication:
Fischbach, A., A. Kruger, S. Hampp, G. Assmann, L. Rank, M. Hufnagel, M. T. Stockl, J. M. F. Fischer, S. Veith, P. Rossatti, M. Ganz, E. Ferrando-May, A. Hartwig, K. Hauser, L. Wiesmuller, A. Bürkle and A. Mangerich. "The C-terminal domain of p53 orchestrates the interplay between non-covalent and covalent poly(ADP-ribosyl)ation of p53 by PARP1." Nucleic Acids Research, Volume 46, Issue 2, 25 January 2018, Pages 804–822, https://doi.org/10.1093/nar/gkx1205

Facts:

• Biologists and chemists from the University of Konstanz, the University of Ulm and the Karlsruhe Institute of Technology (KIT) decipher molecular mechanism of the cell with significance in tumour biology.

• Current publication in the scientific journal Nucleic Acids Research (NAR):
Nucleic Acids Research, Volume 46, Issue 2, 25 January 2018, Pages 804–822, https://doi.org/10.1093/nar/gkx1205

• The tumor suppressor protein p53, the "guardian of the genome", is modified through interaction with the enzyme PARP-1, the "caretaker of the genome". This modification has far-reaching implications for the regulation of biochemical and cellular functions of p53.

• Project headed by Konstanz biologist PD Dr Aswin Mangerich at the Chair of Molecular Toxicology of the Professor Alexander Bürkle. Completed doctoral project by Dr. Arthur Fischbach.

• Funded by the German Research Foundation (DFG), the Collaborative Research Center 969 (SFB 969), as well as the Research School Chemical Biology and the Zukunftskolleg at the University of Konstanz.

Note to editors:
A picture is available for download here: https://cms.uni-konstanz.de/fileadmin/pi/fileserver/2018/Bilder/W%C3%A4chter_des...

Caption:
A molecular mechanism deciphered: Once activated, e.g. through DNA damage, the enzyme PARP-1 forms the biopolymer PAR (poly(ADP-ribose)). PAR, in turn, initiates binding to the tumour-suppressor protein p53 in the region of the C-terminal domain (CTD). PARP-1 will then modify p53 with the PAR biopolymer. As depicted in the lower part of the picture, these molecular processes have far-reaching implications for a number of biochemical and cellular functions that play an important role in tumour biology.
Picture: Aswin Mangerich, University of Konstanz

Contact
University of Konstanz
Communications and Marketing
Phone: + 49 7531 88-3603
E-Mail: kum@uni-konstanz.de

Julia Wandt | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht Straight to the heart
24.06.2019 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft

nachricht Fungus produces highly effective surfactant
21.06.2019 | Friedrich-Schiller-Universität Jena

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fraunhofer IDMT demonstrates its method for acoustic quality inspection at »Sensor+Test 2019« in Nürnberg

From June 25th to 27th 2019, the Fraunhofer Institute for Digital Media Technology IDMT in Ilmenau (Germany) will be presenting a new solution for acoustic quality inspection allowing contact-free, non-destructive testing of manufactured parts and components. The method which has reached Technology Readiness Level 6 already, is currently being successfully tested in practical use together with a number of industrial partners.

Reducing machine downtime, manufacturing defects, and excessive scrap

Im Focus: Successfully Tested in Praxis: Bidirectional Sensor Technology Optimizes Laser Material Deposition

The quality of additively manufactured components depends not only on the manufacturing process, but also on the inline process control. The process control ensures a reliable coating process because it detects deviations from the target geometry immediately. At LASER World of PHOTONICS 2019, the Fraunhofer Institute for Laser Technology ILT will be demonstrating how well bi-directional sensor technology can already be used for Laser Material Deposition (LMD) in combination with commercial optics at booth A2.431.

Fraunhofer ILT has been developing optical sensor technology specifically for production measurement technology for around 10 years. In particular, its »bd-1«...

Im Focus: The hidden structure of the periodic system

The well-known representation of chemical elements is just one example of how objects can be arranged and classified

The periodic table of elements that most chemistry books depict is only one special case. This tabular overview of the chemical elements, which goes back to...

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Non-invasive view into the heart

24.06.2019 | Medical Engineering

Fingerprint spectroscopy within a millisecond

24.06.2019 | Trade Fair News

Straight to the heart

24.06.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>