Abstract
Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER.
Highlights
In eukaryotic cells exposed to UV-irradiation, two different modes of nucleotide excision repair (NER) are activated: (I) global genomic-nucleotide excision repair (GG-NER) and (II)transcription-coupled-nucleotide excision repair (TC-NER), which is involved in the recognition of distorted DNA and determines both spatial and time-related preferences [1,2]
In this review we introduce the most important post-translational modifications (PTMs) that play an essential role in NER, we principally emphasize the regulatory role of ubiquitylation during GG-NER and TC-NER
A key function is attributed to CSB, the presence of which at the RNAPII-stalled region is regulated by UVSSA (UV-stimulated scaffold protein A) and CSA E3 ligase as well as USP7 DUB
Summary
In eukaryotic cells exposed to UV-irradiation, two different modes of nucleotide excision repair (NER) are activated: (I) global genomic-nucleotide excision repair (GG-NER) and (II). In GG-NER, XPC (Xeroderma pigmentosum, complementation group C), which is one of the first sensors of DNA damage, can be either polyubiquitylated at K48-linked chains by CRL4DDB2 or at K63-linked chains by RNF111 (Ring Finger Protein 111, known as Arkadia), resulting in different outcomes. These sites can be deubiquitylated by UBP12 (Ubiquitin specific protease 12) and USP24 (Ubiquitin specific peptidase 24) (at K48) as well as by USP7 These processes jointly contribute to the preservation of genome integrity, which may prevent cancerous malformations
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