TY - JOUR

T1 - Nucleotide excision repair

T2 - From molecular defects to neurological abnormalities

AU - Krasikova, Yuliya

AU - Rechkunova, Nadejda

AU - Lavrik, Olga

N1 - Funding Information: Funding: This study was funded by the Russian Science Foundation, grant number 21-64-00017 (for N.R. and O.L.), and by the Program of Fundamental Scientific Research of the State Academies of Sciences (no. 0245-2021-0009). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6/2

Y1 - 2021/6/2

N2 - 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 au-tosomal 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 regard-ing NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.

AB - 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 au-tosomal 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 regard-ing NER involvement in oxidative DNA lesion repair. Finally, we highlight how mitochondrial dysfunction may be associated with XP.

KW - Base excision repair

KW - Mitophagy

KW - Neurodegeneration

KW - Nucleotide excision repair

KW - Oxidative stress

KW - Xeroderma pigmentosum

KW - DNA Repair

KW - Humans

KW - Mitochondria/genetics

KW - Neurodegenerative Diseases/genetics

KW - Ultraviolet Rays/adverse effects

KW - Xeroderma Pigmentosum/genetics

UR - http://www.scopus.com/inward/record.url?scp=85107442906&partnerID=8YFLogxK

U2 - 10.3390/ijms22126220

DO - 10.3390/ijms22126220

M3 - Review article

C2 - 34207557

AN - SCOPUS:85107442906

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 12

M1 - 6220

ER -