Nucleotide Excision Repair in Eukaryotes

Abstract

Nucleotide excision repair (NER) is the main pathway used by mammals to remove bulky DNA lesions such as those formed by UV light, environmental mutagens, and some cancer chemotherapeutic adducts from DNA. Deficiencies in NER are associated with the extremely skin cancer-prone inherited disorder xeroderma pigmentosum. Although the core NER reaction and the factors that execute it have been known for some years, recent studies have led to a much more detailed understanding of the NER mechanism, how NER operates in the context of chromatin, and how it is connected to other cellular processes such as DNA damage signaling and transcription. This review emphasizes biochemical, structural, cell biological, and genetic studies since 2005 that have shed light on many aspects of the NER pathway. N ucleotide excision repair (NER) is the main pathway responsible for the removal of bulky DNA lesions induced by UV irradiation, environmental mutagens, and certain chemotherapeutic agents. The history of the discovery of NER, its association with genetic disorders, mechanistic features, and relationship with other cellular pathways has been extensively reviewed in 2005 in several articles in DNA Repair and Mutagenesis (Friedberg et al. 2005). Here, I will briefly reiterate how the field of NER developed over the past 50 years and then focus on how our knowledge has progressed since 2005.

Mammalian Transcription-Coupled Excision Repair

“…A lesion-bound complex involving at least the TFIIH, XPA, and RPA proteins provide the structural basis to load and properly orient the structure-specific endonucleases ERCC1/ XPF and XPG, which incise, respectively, the damaged strand 5 0 and 3 0 to the lesion. The consequent 25 -30 nucleotide gap is filled in by the replication machinery and sealed by DNA ligases (Moser et al 2007;Ogi et al 2010;Schärer 2013). At the cellular level, TC-NER or GG-NER deficiency results in UV hypersensitivity.…”

“…It is likely that increased cell death in CS cells in response to UV light is not solely derived from disturbed cellular homeostasis because of a lack of vital transcripts, but that blocked transcription complexes are very cytotoxic structures, which induce a strong damage or persistent signaling cascade. Next to its vital role in protecting cells against a DDR that is too strong (apoptosis or permanent cell-cycle arrest), TC-NER seems also important in preventing UV-induced transcription-associated mutagenesis (Hendriks et al 2010;Schärer 2013).…”

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

“…The NER pathway is responsible for excising and repairing CBPD mutations after UVR, and it is a necessary mechanism that is used to repair a wide range of DNA lesions (14). NER can be categorized into two subpathways: global genome repair (GGR) and transcription-coupled repair (15,16).…”

Global Genome Repair factors controls DNA methylation patterns in Arabidopsis

“…For this we extended our analysis to a mutant affecting CENTRIN2 (CEN2), which is part of the XPC complex (Xeroderma pigmentosum, complementation group C) that recognizes bulky DNA adducts, 7,8 and to a mutant affecting RAD10, which is an endonuclease involved in the dual excision of photoproducts. 1 Using the methylation-dependent restriction enzyme, McrBC, coupled to qPCR, we found that both cen2 and rad10 mutant plants exhibit DNA methylation alterations similar to those observed in several previously identified ddb2-induced Differentially Methylated Regions 6 (DMRs; Fig. 1).…”

“…DNA DAMAGE-BINDING PROTEIN 2 (DDB2) is the main factor involved in the recognition of UV-induced DNA lesions during Global Genome Repair (GGR) in mammals and in plants. 1 In a recent study we reported that, in Arabidopsis, loss of DDB2 function alters DNA methylation patterns at many repeat loci and protein coding genes. We demonstrated that DDB2 acts in a complex with ARGONAUTE 4 (AGO4) to control de novo DNA methylation via the modulation of the local abundance of 24-nt small interfering RNAs (siRNAs).…”