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DNA damage and repair

DNA Damage and Repair

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The mammalian genome is protected against genotoxic insults by a network of DNA-damage response (DDR) mechanisms including different DNA repair and damage signaling pathways, to remove lesions and to activate cell cycle checkpoints. Nucleotide Excision Repair (NER) is an important DNA repair mechanism able to remove a broad range of different types of helix-distorting DNA lesions. NER protects organisms against DNA damage-induced carcinogenesis and premature aging. Its significance is illustrated by the severe clinical consequences associated with inherited defects in NER. Genetic defects in NER give rise to various photo-sensitive syndromes, which include the cancer-prone disease Xeroderma Pigmentosum (XP), the premature ageing Cockayne’s Syndrome (CS), and the UV-sensitive syndrome (UVSS).

Transcription blocking DNA lesions (TBLs) cause cellular dysfunction, senescence and apoptosis, finally resulting in DNA damage induced aging. Cells counteract these deleterious effects by transcription-coupled repair (TCR), which removes RNA polymerase 2 (RNAP2) stalling DNA damage. The severe symptoms associated with inherited TCR defects underscore its importance to health but are strikingly diverse, ranging from mild photosensitivity to severe developmental, neurological and premature aging features. Even though TCR was discovered almost 3 decades ago, surprisingly little is known about the molecular consequence and fate of RNAP2 when stalled at different types of TBLs, how transcription is inhibited and subsequently restarted upon repair. Also why TBLs affect tissues differently and how this relates to aging remains enigmatic.

We apply a multidisciplinary approach to improve our understanding of the molecular mechanism of NER and the impact of NER on biological systems, working from the molecular genetic, biochemical and cell biological level to the level of intact eukaryotic organisms and patients.