Abstract
Nucleotide excision repair (NER) is the most versatile DNA repair pathway, which can remove diverse bulky DNA lesions destabilizing a DNA duplex. NER defects cause several autosomal recessive genetic disorders. Xeroderma pigmentosum (XP) is one of the NER-associated syndromes characterized by low efficiency of the removal of bulky DNA adducts generated by ultraviolet radiation. XP patients have extremely high ultraviolet-light sensitivity of sun-exposed tissues, often resulting in multiple skin and eye cancers. Some XP patients develop characteristic neurodegeneration that is believed to derive from their inability to repair neuronal DNA damaged by endogenous metabolites. A specific class of oxidatively induced DNA lesions, 8,5′-cyclopurine-2′-deoxynucleosides, is considered endogenous DNA lesions mainly responsible for neurological problems in XP. Growing evidence suggests that XP is accompanied by defective mitophagy, as in primary mitochondrial disorders. Moreover, NER pathway is absent in mitochondria, implying that the mitochondrial dysfunction is secondary to nuclear NER defects. In this review, we discuss the current understanding of the NER molecular mechanism and focuses on the NER linkage with the neurological degeneration in patients with XP. We also present recent research advances regarding NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.
Highlights
Human TFIIH binds downstream of RNAPII in the transcription pre-initiation complex [44]. In line with these data, we propose that in TC-Nucleotide excision repair (NER) initiation, TFIIH should bind downstream of RNAPII for subsequent movement on the same damaged strand in the opposite 50 →30 direction (Figure 3B)
This “aging” theory for xeroderma pigmentosum (XP) neurodegeneration is supported by the findings of Lindahl and colleges indicating that DNA exposure to reactive oxygen species (ROS) generates a class of DNA lesions that are normally repaired by NER
Nonbulky oxidative DNA lesions cannot block transcription by RNA pol II [99]; the sible to speculate that XP-C individuals carry out normal transcription-coupled NER (TC-NER), so they can develop only way these lesions could cause neurodegeneration is through a progressive decrease in neurological symptoms much later in comparison with other XP patients [66]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. DNA damage can be caused by endogenous factors such as replication errors or cellular oxidative metabolism products from mitochondria or inflammation [1]. The lesions can disrupt the basic processes of DNA metabolism by blocking replication and transcription. To counteract these adverse effects, eukaryotic cells are equipped with several DNA repair mechanisms acting on different types of DNA damage [2,3]. Byproducts of the ATP formation give rise to reactive oxygen species (ROS), which can cause many types of oxidative DNA damage to genomic and mitochondrial DNA [18,19]. It is widely accepted that the accumulation of oxidative DNA lesions is the cause of the neuropathology that takes place with aging as in several neurodegenerative disorders. We describe the way in which mitochondrial dysfunction is believed to be associated with XP
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