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Review
. 2021 Jun 9;22(12):6220.
doi: 10.3390/ijms22126220.

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Yuliya Krasikova  1 , Nadejda Rechkunova  1 , Olga Lavrik  1   2
Affiliations
Review

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Yuliya Krasikova et al. Int J Mol Sci. .

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.

Keywords: base excision repair; mitophagy; neurodegeneration; nucleotide excision repair; oxidative stress; xeroderma pigmentosum.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of DNA photoproducts caused by sunlight. The majority of cyclobutane pyrimidine dimers (CPDs) is formed between adjacent thymine residues (TT) but can eventually arise between adjacent T and C, C and T, or C and C, depending on the wavelength, irradiation dose, and adjacent sequences. CPD can be formed with cis-syn isomer representing large majority of CPDs within duplex DNA, and trans-syn occurring exclusively within single-stranded DNA. Pyrimidine-(6-4)-pyrimidone photoproducts (6-4PPs) are generated preferentially in nucleotide pairs TC, CC, and TT, with the ratio and yields depending on irradiation wavelength and adjacent sequences [8]. This figure is based on several studies [8,22].
Figure 2
Figure 2
An overview of the damage recognition step of nucleotide excision repair (NER). (A) Global genome NER (GG-NER) can search for damage anywhere in the genome throughout the cell cycle. The UV-DDB protein recognizes CPD or 6-4PP, directly binds to it through its DDB2 subunit, and facilitates efficient recognition of the lesion by the XPC–RAD23B–CETN2 complex. The DDB1 subunit is also a connector protein for ubiquitin ligase CUL4, which ubiquitinates DDB2 and XPC [33]. (B) Transcription-coupled NER (TC-NER) is responsible for accelerated repair of lesions in the template DNA strand of actively transcribed genes only. The CSB protein and then proteins CSA and UVSSA bind to DNA damage stalled RNAPII. CSB and CSA associate with CRL ubiquitin ligase and contribute to the ubiquitination of the RNAPII RPB1 subunit at K1268. This ubiquitination stimulates the association of TFIIH with the stalled RNAPII through a transfer mechanism that also involves UVSSA-K414 ubiquitination [9,35].
Figure 3
Figure 3
Schematic view of the damage verification step of NER and pre-incision complex formation. (A) GG-NER. TFIIH initially interacts with XPC’s N terminus by means of p62 subunits, then tumbles to XPC’s C terminus, where the interaction with XPB promotes its binding to a duplex part. XPA releases an inhibitory CAK module and together with XPG stimulates XPD activity [45]. The XPD helicase binds to the damaged strand and starts to a repair bubble formation [7]. When XPD gets to the lesion and stalls on it, XPC is displaced, and XPG binds to the 3′ edge of the repair bubble. (B) TC-NER. XPC and UVSSA share an interaction surface on the p62 subunit of TFIIH [41]. RNAPII moves in the 3′→5′ direction on the damaged strand, then, after its lesion stalling and assembly of factors CSB, CSA, and UVSSA, the latter promotes TFIIH binding downstream of RNAPII [37]. Thereafter, XPA and XPG stimulate XPD activity, and TFIIH starts to move in the 5′→3′ direction and may “push” RNAPII for a backtracking movement. (C) The NER pre-incision complex (PIC): TFIIH stalls on the lesion-bearing strand, RPA covers the undamaged strand, XPA marks the 5′ edge of the repair bubble, XPG marks the 3′ edge of the repair bubble, and XPF–ERCC1 binds behind XPA.
Figure 4
Figure 4
Late NER stages: dual incision, resynthesis, and ligation. The first incision is carried out by XPF–ERCC1 from the 5′ side to the lesion site. Then, replication machinery is loaded, and repair synthesis can be initiated. Possible sets of replication machines: DNA polymerase δ, PCNA, and RFC; DNA polymerase ε, PCNA, and a modified form of RFC; or DNA polymerase κ, ubiquitinated PCNA, and XRCC1. Halfway gap resynthesis is followed by a second incision by XPG. After repair synthesis is completed, nick sealing is performed by DNA ligase I or by the DNA ligase IIIα–XRCC1 complex.
Figure 5
Figure 5
Chemical structures of common oxidative DNA lesions. (A) Guanine oxidation products. Products of two-electron guanine oxidation are 8-oxo-7,8-dehydroguanine (8-oxoG) and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih). Four-electron guanine oxidation products are 5-guanidinohydantoin (Gh), spiroiminodihydantoin (Sp), 2,5-diamino-4H-imidazol-4-one (Iz), and 2,2,4-triamino-5(2H)-oxazolone (Oz). (B) Formation of 8,5′-cyclo-2′-deoxyguanosine (cyclic guanosine, cdG) through hydroxyl radical (HO•) oxidation under hypoxic conditions.
Figure 6
Figure 6
SIRT1–PARP1 reciprocal regulation within the nuclear–mitochondrial crosstalk occurs during normal cellular metabolism.
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