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IMBB researchers reveal a novel function for Nucleotide Excision Repair in mammalian development
Research carried out at the Institute of Molecular Biology and Biotechnology-FORTH and published today in the Proceedings of National Academy of Sciences USA reveals that proteins involved in Nucleotide Excision Repair (NER) activate the expression of key growth factors during postnatal development.
Integrity of the genome is critical for normal cellular function but the DNA is continually challenged by intrinsic and extrinsic genotoxic factors. To counteract DNA damage, cells have evolved complementary DNA repair systems ensuring that the genome remains functionally intact and is faithfully transmitted to progeny. Nucleotide excision repair (NER) is a major DNA repair mechanism that cells employ to remove a wide class of bulky, DNA-distorting lesions from the genome.
The importance of NER defects in man is illustrated by rare syndromes that either show increased cancer predisposition or dramatic features of accelerated aging. However, with the exception of cancer, the links between defects in NER and developmental abnormalities are not well understood. For instance, it has been puzzling why some, but not all, defects in NER lead to developmental abnormalities and how such pathological outcomes manifest in some, but not all, organs of NER patients.
Using genetically modified mice that reproduce the defects of NER observed in patients, the IMBB researchers Irene Kamileri, working together with the head of the research team Prof. George Garinis, revealed that certain NER factors, in addition to their role in DNA repair, are important for the transcriptional regulation of growth factors during postnatal development. The IMBB researchers have found that the NER-deficient mice demonstrate striking similarities with animals carrying defects in transcriptional regulation but have otherwise normal DNA repair function. This surprising finding let them to hypothesize that NER maintains previously unknown functions beyond DNA repair. The discovery that proteins involved in NER are capable of activating the expression of growth genes during postnatal development confirmed their hypothesis.
This is the first time where DNA repair mechanisms are shown to be directly involved in postnatal growth revealing a causal mechanism underlying the pathogenesis of NER syndromes. The findings are also expected to provide key insight into the molecular mechanism underlying progeria and cancer predisposition, which are frequently observed in patients with defects in NER.
For more information please contact:
Dr. George A. Garinis, Associate Professor, Dept. of Biology, U. Crete and Group leader at IMBB.
(Tel.: +30 2810391246; Email: email@example.com)