Epigenetic Events in Nucleotide Excision Repair

• Applicant: Dr. Holger Richly
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252235824

One of the important functions in the life of a cell is to protect the structural integrity of DNA, thereby safeguarding the genetic information contained therein. DNA is exposed to many sources of damage, both internally in the form of reactive oxygen species and spontaneous hydrolysis of nucleotides, or externally from chemical or physical agents such as UV or ionising radiation. This leads to different types of lesions and potentially mutations in the DNA sequence. One of the multiple types of DNA damage repair pathways is nucleotide excision repair (NER). Defects in NER cause a high photosensitivity and are responsible for skin cancers such as in the Xeroderma pigmentosum (XP) phenotype. NER functions in two modes; repair of lesions over the entire genome, referred to as global genome NER (GG NER), and repair of transcription-blocking lesions present in transcribed DNA strands, hence called transcription-coupled NER (TC NER). Both branches of NER impact on the epigenetic status of the genomic regions of the lesions. Conversely it is comprehensive that epigenetic mechanisms play a crucial role in orchestrating the repair process. A deeper understanding of the epigenetic events taking place during NER will thus open new avenues for therapeutic intervention in skin cancer. Our previous studies uncovered the epigenetic mechanism involved in GG NER. In particular, the Polycomb repressive complex 1 (PRC1) and its antagonist ZRF1 cooperate with members of the Xeroderma pigmentosa family in directing the recognition of DNA lesions. Likewise, in TC NER PRC1 and ZRF1 are causing the proteasomal degradation of paused Polymerase II and the function of both components is linked to the endoribonuclease DICER, which we suggest is instrumental in generating heterochromatin in genomic regions close to the DNA lesions. Our work goes significantly beyond the state of the art in DNA repair research and will provide important new insights in the molecular mechanisms of NER.

• DFG Programme: Research Grants