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Turn that alarm off!

Munich, 03/12/2013

Cells react to stress by alerting well known defense and repair systems, but how the alarm is turned off has long remained a mystery. The crucial enzymes involved have now been identified, and if one of them is missing it causes a serious neurodegenerative disease.

When an alarm goes off, there’s no time to waste. This rule also holds for cells. When the genetic material in a cell suffers radiation damage, for example, it must be repaired as quickly as possible. If the damage is extensive, the cell must be induced to self-destruct by programmed cell death. These reactions are controlled by damage detectors and complex signal transduction pathways. The earliest steps in these signaling pathways involve diverse enzymatic modifications of specific targets. The most immediate response to DNA damage is thought to be the attachment of the functional group ADP-ribose to certain proteins in the cell nucleus.

“ADP-ribosylation acts as an emergency signal and has a major impact on all the subsequent steps in the responses that mediate the removal and repair of DNA damage,” says Professor Andreas Ladurner of the Adolf Butenandt Institute at the LMU. His group is particularly interested in the mechanisms that set off this alarm bell in the cell. Many of the factors that are recruited to damage sites as a result of ADP-ribosylation and signal other proteins to take remedial action have been identified. Clearly, however, the alert must also be lifted at some point to allow the cell machinery to return to its normal functional state. “The enzymes involved in this last step have so far remained unknown,” says Ladurner. But he and his team have now been able to close this gap in our knowledge.

In the latest online issue of the journal Nature Structural & Molecular Biology, Ladurner and his colleagues demonstrate that, in human cells, three members of the so-called macrodomain protein family are responsible for the removal of ADP-ribose moieties from its targets. With the aid of structural analysis by X-ray diffraction, the team has elucidated their mode of action, and identified homologs in many other organisms. One of the most surprising findings was that other members of the macrodomain family can recognize the modification, but are unable to remove it. This implies that first different members of the same protein family act in the initial recognition of ADP-ribosylation as an alarm signal. Next, other members act in the elimination of the marker after the acute problem has been resolved.

Loss of enzyme results in lethal disease
Since ADP-ribosylation is known to be involved in intracellular signaling pathways triggered by many different kinds of stress, genetic alterations or errors that impinge on the process would be expected to have clinical consequences. “In a separate investigation, carried out in cooperation with English and American colleagues, we studied the genetics of a hereditary disease found in several Iranian families. The disorder is characterized by a progressive type of neurodegeneration that leads to death during childhood. We were able to show that this condition is due to the lack of one of the newly identified enzymes,” reports Dr. Gyula Timinszky, a group leader in Ladurner’s team and one of the corresponding authors of that study, which appears in the EMBO Journal.

The scientists suspect that other neurodegenerative diseases may also be attributable to defects in ADP-ribosylation signaling networks. Following elucidation of the structures of the new enzymes, detailed studies of the mechanism of the ADP-ribosylation reaction, and its cell biological and clinical significance, are now on the agenda. “To put it in a nutshell: we have finally pinpointed the enzymes that researchers in our field have been seeking for the past 30 years. We can now study the signal pathways they participate in from entirely new angles,” Ladurner concludes. (Nature Structural & Molecular Biology, Advance Online Publication 10.3.2013 and The EMBO Journal 2013) göd

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