Systemic DNA-damage responses in development and aging

BN Seminar
 
Speaker: Björn Schumacher (University of Cologne)

Subject: Systemic DNA Damage responses in development and aging

Location: TU Delft

Date: Thursday, 29.10.2015, 16:00-17:00

Author: Edgar Schönfeld

It is estimated that each DNA molecule experiences tens of thousands lesions daily. While unrepaired damages foster ageing, erroneous repair promotes cancer. Mutations in nucleotide excision repair (NER) pathways, however, result in impaired development. Mutations in specific proteins involved in global-genome NER (GG-NER) result in the syndrome Xeroderma Pigmentosum, which is characterized by an enormously increased risk of UV-light-induced skin cancer. Cockayne Syndrome, on the other hand, is attributed to defects in transcription-coupled repair (TCR) and entails premature aging.

schumacher_03_2015
Simplified working principle of GG-NER and TCR (source: http://cecad.uni-koeln.de/Dr-Bjoern-Schumacher.107.0.html)

Prof. Schumacher is interested in understanding the processes that are responsible for somatic maintenance and thereby ageing. To address this question, the worm C.elegans was chosen as an animal model, as the GG-NER and TCR pathways are evolutionarily conserved in this animal. Xeroderma Pigmentosum is caused among others by point mutations in the gene XPC, while Cockayne Syndrome develops as a result of mutations in the genes CSA or CSB. Prof. Schumacher’s team radiated C. elegans with UV-light. Worms with mutations in XPC developed normally, despite being sterile. Worms with defective CSB, on the other hand, developed a healthy germ line, but mitosis in somatic cells was impaired. This suggested that GG-NER is of vital significance for germ cells, while TC-NER is essential for somatic tissues. Previously it was thought that these two branches of NER function during different stages of development. The next step was the identification of genes responding to UV-induced DNA damage. In order to do so the transcriptome of the treated worms was analyzed and a lot of genes proved to be differentially expressed. Parallely the program “Wormpath” was written, which uses statistical methods to identify the network of genetic interactions that correlates most with the observed gene expression pattern. Such a network was found and the genes DAF-16 and DAF-2 played a pivotal role in it. These genes are also known for being involved in aging. DAF-2 mutant worms live twice as long as wild-type C.elegans. It became evident that DAF-2 activates DAF-16 if persistent DNA-damage is present. The researchers also demonstrated that DAF-16 helps to overcome damage-induced developmental arrest through enhancement of tissue functionality. DAF-16 activation alone is sufficient to promote developmental growth after UV-induced damage. In this way, DAF-16 ensures that cells can develop normally even in the presence of persistent DNA-damage, even in the absence of DNA-repair. This damage tolerance ensures tissue functionality amidst the accumulating number of mutations in the process of aging.
What I find particularly interesting is that there seem to be mechanisms that counteract cell cycle arrest, which is meant to give the cell time to repair its DNA. In my eyes, this implies that cells are willing to sacrifice a bit of their genomic integrity to guarantee the functionality of the whole tissue. Apart from that, the “Wormpath” programme impresses me.

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