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How Cells React to DNA Damage: MDC Researchers Decode Dual Signaling Pathway for the Activation of the Survival Factor NF-kappaB

Upon damage to the genomic DNA, repair enzymes and gene regulators are activated that determine the fate of the affected cells. Researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, have now shown how the transcription factor NF-kappaB, which coordinates a cellular survival program, is activated by DNA damage. Dr. Michael Hinz, Dr. Michael Stilmann and Professor Dr. Claus Scheidereit have uncovered a dual signaling pathway which is used for signal transmission. DNA damage-induced NF-kappaB activation is associated with the resistance of cancer cells to radiation and chemotherapy. (Molecular Cell, DOI 10.1016/j.molcel.2010.09.008)*.

The human genome is
constantly endangered by ultraviolet
(UV) radiation, chemicals and toxic metabolic products. To prevent irreversible
genomic defects, human cells have control systems that recognize DNA lesions
within seconds and initiate their fast repair.

DNA damage
induces two opposing cellular reactions which determine the fate of the
affected cell. On the one hand, cells can launch a suicide program (programmed
cell death) in case of unsuccessful DNA repair. This ensures that damaged DNA
is not passed on to daughter cells upon cell division.

On the
other hand, cells activate the transcription factor NF-kappaB, which
coordinates a survival program and counteracts programmed cell death. This
likely prevents loss of cells which can undergo successful DNA repair.

Two ways lead to NF-kappaB

In 2009,
the team of Professor Scheidereit discovered that NF-kappaB activation requires
the DNA damage sensor protein PARP-1. PARP-1 detects DNA damage within seconds
and assembles several proteins as well as additional macromolecules to form a
nuclear signaling complex, which acts as initial trigger of the NF-kappaB activation
process (Molecular Cell 36, 365–378,
November 13, 2009).

Now Dr.
Hinz and Dr. Stilmann have identified a second signaling cascade, acting in parallel,
that is required for NF-kappaB activation as well. The latter is elicited by
the DNA damage sensor protein ATM.

ATM is
activated by DNA damage in the nucleus, migrates to the cytoplasm and provokes
the formation of specific protein complexes. Subsequently, signaling proteins known
to be essential for NF-kappaB activation, such as IKKgamma and IKKbeta, are
modified biochemically, e.g. through the attachment of phosphate groups or a
small regulatory protein (ubiquitin). As the MDC researchers showed, these
modifications are a crucial step in the signaling process.

The
researchers demonstrated that signaling complexes induced by PARP-1 and ATM
contain a number of enzymes which in turn catalyze the biochemical
modifications of the signaling proteins. A coordinated interplay of all
signaling components is essential for efficient signal transduction. NF-kappaB
can only be activated when both PARP-1 and ATM-dependent signaling branches are
active.

NF-kappaB: Responsible for tumor therapy
resistance?

Several
experimental observations indicate that activation of the NF-kappaB-mediated
survival program plays a key role in tumor cell development and survival.
“Treatment of tumor diseases is often impaired because chemotherapy and radiation therapy do not elicit the
desired effect. Activation of the survival factor NF-kappaB may be one of the
causes of this therapy resistance,” Professor Scheidereit said. “If this
hypothesis is confirmed, the elucidation of the NF-kappaB signaling pathway may
lead to new targets for pharmacological development and improvement of existing
therapy concepts.”

*A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation Michael Hinz1*, Michael Stilmann1*, Seda Çöl Arslan1,2, Kum Kum Khanna3 Gunnar Dittmar4, and Claus Scheidereit1,5

1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany; 2Humboldt University, Institute of Biology, Chausseestrasse 117, 10115 Berlin; 3Signal Transduction Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia; 4Mass spectrometry facility, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin

* These authors contributed equally to this work

Barbara
Bachtler
Press
and Public Affairs
MaxDelbrück
Center for Molecular Medicine (MDC)
Berlin-Buch
Robert-Rössle-Straße
10; 13125 Berlin; Germany
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