Coordination of DNA Base Excision Repair by Protein-Protein Interactions

Moor, Nina; Lavrik, Olga I.

doi:10.5772/intechopen.82642

Cited by 7 publications

(3 citation statements)

References 117 publications

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“…During BER, DNA intermediates are bound by one or several BER enzymes (BER mechanism is reviewed extensively, see [78][79][80][81] for example). Thus, a question arises: how NER can be involved in oxidative damage repair?…”

Section: Ner Impact In Oxidative Lesions Repairmentioning

confidence: 99%

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Krasikova

Rechkunova

Lavrik

2021

IJMS

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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.

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Section: Ner Impact In Oxidative Lesions Repairmentioning

confidence: 99%

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Krasikova

Rechkunova

Lavrik

2021

IJMS

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“…The efficient repair of damaged DNA via the multistep process of each of the subpathways requires the coordinated action of enzymes catalyzing the sequential individual reactions [2][3][4]. Coordination is facilitated by multiple protein-protein interactions, reviewed previously [13,44]. Physical interaction and functional interplay between two major BER enzymes, APE1 and Polβ, were shown by various [13,31,38,41,45].…”

Section: Discussionmentioning

confidence: 99%

Functional Role of N-Terminal Extension of Human AP Endonuclease 1 In Coordination of Base Excision DNA Repair via Protein–Protein Interactions

Moor

Васильева

Lavrik

2020

IJMS

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Human apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions in base excision DNA repair (BER) and other cellular processes. Its eukaryote-specific N-terminal extension plays diverse regulatory roles in interaction with different partners. Here, we explored its involvement in interaction with canonical BER proteins. Using fluorescence based-techniques, we compared binding affinities of the full-length and N-terminally truncated forms of APE1 (APE1NΔ35 and APE1NΔ61) for functionally and structurally different DNA polymerase β (Polβ), X-ray repair cross-complementing protein 1 (XRCC1), and poly(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP1), in the absence and presence of model DNA intermediates. Influence of the N-terminal truncation on binding the AP site-containing DNA was additionally explored. These data suggest that the interaction domain for proteins is basically formed by the conserved catalytic core of APE1. The N-terminal extension being capable of dynamically interacting with the protein and DNA partners is mostly responsible for DNA-dependent modulation of protein–protein interactions. Polβ, XRCC1, and PARP1 were shown to more efficiently regulate the endonuclease activity of the full-length protein than that of APE1NΔ61, further suggesting contribution of the N-terminal extension to BER coordination. Our results advance the understanding of functional roles of eukaryote-specific protein extensions in highly coordinated BER processes.

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“…The DNA polymerase β (Polβ) is the smallest enzyme of the BER pathway. Several enzymes involved in the BER pathway interact with Polβ like DNA glycosylase, APE, PKNP, FEN1, PARP, XRCC1, [ 8 ] etc. In our previous study, we reported an ovarian cancer-specific mutation in the DNA Polβ, with the deletion in exon number 11–13, which could be detectable at an earlier stage of cancer [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

PA1 cells containing a truncated DNA polymerase β protein are more sensitive to gamma radiation

Patra¹,

Nag

Chakraborty

et al. 2022

Radiat Oncol J

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Purpose: DNA polymerase β (Polβ) acts in the base excision repair (BER) pathway. Mutations in DNA polymerase β (Polβ) are associated with different cancers. A variant of Polβ with a 97 amino acid deletion (PolβΔ), in heterozygous conditions with wild-type Polβ, was identified in sporadic ovarian tumor samples. This study aims to evaluate the gamma radiation sensitivity of PolβΔ for possible target therapy in ovarian cancer treatment.Materials and Methods: PolβΔ cDNA was cloned in a GFP vector and transfected in PA1 cells. Stable cells (PA1PolβΔ) were treated with 60Co sourced gamma-ray (0–15 Gy) to investigate their radiation sensitivity. The affinity of PolβΔ with DNA evaluated by DNA protein in silico docking experiments.Result: The result showed a statistically significant (p < 0.05) higher sensitivity towards radiation at different doses (0–15 Gy) and time-point (48–72 hours) for PA1PolβΔ cells in comparison with normal PA1 cells. Ten Gy of gamma radiation was found to be the optimal dose. Significantly more PA1PolβΔ cells were killed at this dose than PA1 cells after 48 hours of treatment via an apoptotic pathway. The in silico docking experiments revealed that PolβΔ has more substantial binding potential towards the dsDNA than wild-type Polβ, suggesting a possible failure of BER pathway that results in cell death.Conclusion: Our study showed that the PA1PolβΔ cells were more susceptible than PA1 cells to gamma radiation. In the future, the potentiality of ionizing radiation to treat this type of cancer will be checked in animal models.

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Coordination of DNA Base Excision Repair by Protein-Protein Interactions

Cited by 7 publications

References 117 publications

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Nucleotide Excision Repair: From Molecular Defects to Neurological Abnormalities

Functional Role of N-Terminal Extension of Human AP Endonuclease 1 In Coordination of Base Excision DNA Repair via Protein–Protein Interactions

PA1 cells containing a truncated DNA polymerase β protein are more sensitive to gamma radiation

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