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A stowaway for damage control

New molecule and new enzyme in bacteria discovered

Munich, 04/25/2008

Cancer and other serious diseases are the result of damages in the DNA where our genetic information is stored. In higher organisms the molecule is, therefore, checked on a regular basis and – if possible – repaired. Previous results suggested that bacteria employ similar mechanisms with the help of protagonists like DisA, the “DNA integrity scanning protein A”. A research team under the lead of Professor Karl-Peter Hopfner at Ludwig-Maximilians-Universität (LMU) München has now analyzed the three-dimensional structure of this important protein. As reported in the science journal Molecular Cell, the researchers were in for a surprise: Bound to DisA they found a hitherto unknown molecule. This cyclic di-adenosine phosphate or c-di-AMP is synthesized by DisA and reminiscent of but distinct from c-di-GMP, another bacterial regulator of complex cellular processes. “It’s rare enough to discover a new molecule,” says Hopfner. “But here we have found an unknown enzyme function as well: the synthesis of c-di-AMP by DisA. Our results indicate that c-di-AMP has basic functions in bacteria – which would make our find even more important.”

The maintenance and stability of the genetic information is fundamental to all kingdoms of life. Numerous types of DNA damage are repaired by a variety of mechanisms to maintain genetic integrity. In eukaryotes like humans so-called DNA damage checkpoints closely monitor DNA and trigger cellular responses – even cell death if the damage is beyond repair. “The deactivation of DNA repair and DNA damage checkpoint systems is often linked to cancer and premature aging syndromes,” says Hopfner. “In our study we have analyzed the structure and function of DisA – and uncovered a set of remarkable features.” The researchers show that DisA synthesizes the molecule c-di-AMP and that this activity is strongly suppressed by specific DNA structures which are typical for a stalled replication of the genetic material. “It seems that low levels of c-di-AMP indicate DNA damages,” says Hopfner. “These results raise the possibility that DisA controls a prerequisite for cell division, the DNA replication, by the amount of c-di-AMP synthesis. We suspect that c-di-AMP fulfils other functions as well and that DisA is not the only c-di-AMP cyclase, an enzyme with the ability to produce this molecule.”

“Structural biochemistry of a prokaryotic checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates”,
Gregor Witte, Sophia Hartung, Katharina Büttner, and Karl-Peter Hopfner
Molecular Cell, 25 April 2008

Professor Dr. Karl-Peter Hopfner
Gene Center at LMU
Tel.: +49-89 -2180-76953
Fax: +49-89 -2180-76999

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