Cancer researchers of the Max Delbr-ck Center for Molecular Medicine (MDC) Berlin-Buch have gained new insights into how cells react to DNA damage. Dr. Michael Stilmann, Dr. Michael Hinz and Professor Claus Scheidereit have shown that the protein PARP-1, which detects DNA damage within seconds, activates the transcription factor NF-kappaB, a well-known regulator of gene expression. NF-kappaB triggers a survival program, which blocks programmed cell death. The activation of NF-kappaB is thought to be one of the potential causes for tumor cell resistance to chemo and radiation therapy. (Molecular Cell, online, doi 10.1016/j.molcel.2009.09.032; Preview: doi 10.1016/j.molcel.2009.10.022).
The DNA of each human cell is damaged many times every day. DNA lesions can be caused by ultraviolet radiation, errors in cell division, DNA-damaging chemicals or intracellular metabolic products. Damaged chromosomal DNA can ultimately be the cause for serious diseases, such as cancer.
However, cells have developed complex systems that recognize DNA lesions within seconds and ensure that the damage will be repaired. In case of massive DNA damage, the affected cell can be destroyed by initiating apoptosis (programmed cell death).
Apoptosis is a cellular program which drives defective cells to commit suicide, thus protecting the organism as a whole. Another regulator of gene expression, the transcription factor p53 - also known as the "guardian of the genome" - has a key function in the activation of programmed cell death. But p53 is not always successful in switching on the protective program.
NF-kappaB opposes the function of p53, in turn activating a survival program which protects the damaged cells from destruction. The activation of this program by NF-kappaB is considered to be one of the possible causes for resistance of tumor cells to chemo or radiation therapy.
The transcription factor NF-kappaB not only regulates cell survival programs, it also plays an important role in the immune system and in inflammatory processes. NF-kappaB can be switched on by a number of extracellular and intracellular stimuli.
Such stimulation alters the activity of protein-regulated signaling pathways, which ultimately activate NF-kappaB. The process of signal transduction initiated by external physiological stimuli has been well characterized in recent years.
However, it was not understood how NF-kappaB is switched on by DNA damage. MDC researchers have now succeeded in illuminating this particular signaling pathway.