Nucleotide excision repair: interplay between nuclear compartmentalization, histone modifications and signaling
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Abstract
Maintaining the integrity of genetic information is one of the crucial functions of the cell. Depending on the type of DNA damage, there are several repair pathways dedicated to a quick and efficient repair of the damage. A major source of DNA damage is exposure to UV light, which causes formation of 6’-4’photoproducts and pyrimidine dimers. These are bulky DNA adducts that cause distortion of the helix structure. Such lesions are repaired by Nucleotide Excision Repair (NER). Nucleotide Excision Repair occurs by two sub-pathways, depending on the genomic location of the lesion. Transcription coupled NER (TC-NER) repairs lesions in actively transcribed genes, which global genomic NER (GG-NER) can repair all types of lesions. These two pathways differ in their recognition step. Lesion recognition is followed by verification of damage, excision of the damaged strand, and refilling of the gap by DNA synthesis. An important unanswered question in the field of NER is how the removal of lesions occurs in the context of chromatin structure. Recognition of lesions in heterochromatin requires a decondensation of chromatin to enable access by repair factors. Additionally, lesion recognition requires cascades of recruitment of the various proteins, in a tightly regulated and synchronized manner. We show that the recognition step during GG-NER consists of a ZRF1-DICER-MMSET axis linking lesion recognition via DDB2 to lesion verification via XPA followed by subsequent repair. ZRF1 recognizes the H2AK119 ub mark set by the UV-RING1B complex. This results in translocation of the lesion to the nucleolus, and remodeling of the complex to the UV-CUL4A complex. Formation of this complex enables the next phase of ubiquitylation that regulates NER repair proteins. ZRF1 in turn also contributed to chromatin decondensation through recruitment of DICER. DICER enables relaxation of chromatin structure in a PARP1 dependent manner. It also recruits MMSET, which sets the H4K20me2 mark. This histone mark serves as a tethering platform for recruitment of XPA, a core NER component which is essential for further repair to take place. Thus, we have discovered a novel and essential function for these proteins in NER.