scholarly journals Molecular mechanisms associated with clustered lesion-induced impairment of 8-oxoG recognition by the human glycosylase OGG1

2021 ◽  
Author(s):  
Tao Jiang ◽  
Antonio MONARI ◽  
Elise Dumont ◽  
Emmanuelle Bignon
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Structural Features ◽  
Repair Pathway ◽  
Dna Lesion ◽  
Damage Response ◽  
Base Excision ◽  
Structural Signature ◽  
Dynamics Simulations

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use mu-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5' or 3'. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5' mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

scholarly journals PARP dependent recruitment of RNA methylated at 8-adenosine is linked to base excision repair mechanism

2021 ◽  
Author(s):  
Sona Legartova ◽  
Jana Suchankova ◽  
Eva Bartova
Keyword(s):  
Excision Repair ◽  
Parp Inhibitor ◽  
Dna Lesions ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Repair Mechanism ◽  
Genome Wide ◽  
Damage Response ◽  
Base Excision ◽  
Rna Accumulation

Abstract Methylation of RNAs, especially 6-methyladenosine (m6A)-modified RNAs, plays a specific role in DNA damage response (DDR). Here, we observed that 8-methyladenosine (m8A)-modified RNA is recruited to UVA-microirradiated chromatin, which was reduced by inhibiting both DNA methylation and histone acetylation, especially in later phases of DDR. Most importantly, clinically used PARP inhibitor (PARPi), olaparib, prevents both m8A and m6A RNA accumulation at microirradiated chromatin. Testing the effect of PARPi on the efficiency of BER, NHEJ, and HR repair pathways, we observed that NHEJ repair proteins are down-regulated after PARP inhibition and recruitment of XRCC1, a factor of BER, to DNA lesions was abolished entirely. Conversely, the PARP inhibitor, olaparib, enhanced the genome-wide level of γH2AX that significantly interacted with m8A RNA, similar to DNA. Together, we showed that the recruitment of m6A RNA and m8A RNA to DNA lesions is PARP dependent, similarly as XRCC1 playing a role in the BER mechanism. We found that γH2AX likely stabilizes m8A/m6A RNA-DNA hybrid loops that are formed during PARP-dependent non-canonical m6A/m8A-mediated DNA repair pathway.

scholarly journals Initiation of the ATM-Chk2 DNA damage response through the base excision repair pathway

2015 ◽  
Vol 36 (8) ◽  
pp. 832-840 ◽  
Author(s):  
Wen-Cheng Chou ◽  
Ling-Yueh Hu ◽  
Chia-Ni Hsiung ◽  
Chen-Yang Shen
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Base Excision Repair Pathway ◽  
Damage Response ◽  
Base Excision

scholarly journals Unique structural features of mammalian NEIL2 DNA glycosylase prime its activity for diverse DNA substrates and environments

2020 ◽  
Author(s):  
Brian E. Eckenroth ◽  
Vy Cao ◽  
April M. Averill ◽  
Julie A. Dragon ◽  
Sylvie Doublié
Keyword(s):  
Excision Repair ◽  
Structural Features ◽  
Oxidation Products ◽  
Dna Glycosylases ◽  
Repair Pathway ◽  
Base Loss ◽  
Abasic Sites ◽  
Open Conformation ◽  
Base Excision ◽  
Insight Into

SUMMARYOxidative damage on DNA arising from both endogenous and exogenous sources can result in base modifications that promote errors in replication as well as generate sites of base loss (abasic sites) that present unique challenges to maintaining genomic integrity. These lesions are excised by DNA glycosylases in the first step of the base excision repair pathway. Here we present the first crystal structure of a NEIL2 glycosylase, an enzyme active on cytosine oxidation products and abasic sites. The structure reveals an unusual “open” conformation not seen in NEIL1 or NEIL3 orthologs. NEIL2 is predicted to adopt a “closed” conformation when bound to its substrate. Combined crystallographic and solution scattering studies show the enzyme to be conformationally dynamic in a manner distinct among the NEIL glycosylases and provide insight into the unique substrate preference of the enzyme. Additionally, we characterized three cancer variants of human NEIL2, namely S140N, G230W, and G303R.

scholarly journals Molecular Mechanisms Regulating the DNA Repair Protein APE1: A Focus on Its Flexible N-Terminal Tail Domain

2021 ◽  
Vol 22 (12) ◽  
pp. 6308
Author(s):  
David J. López ◽  
José A. Rodríguez ◽  
Sonia Bañuelos
Keyword(s):  
Dna Repair ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Excision Repair ◽  
Tail Domain ◽  
Protein Protein Interactions ◽  
Key Enzyme ◽  
Dna Repair Protein ◽  
Base Excision

APE1 (DNA (apurinic/apyrimidinic site) endonuclease 1) is a key enzyme of one of the major DNA repair routes, the BER (base excision repair) pathway. APE1 fulfils additional functions, acting as a redox regulator of transcription factors and taking part in RNA metabolism. The mechanisms regulating APE1 are still being deciphered. Structurally, human APE1 consists of a well-characterized globular catalytic domain responsible for its endonuclease activity, preceded by a conformationally flexible N-terminal extension, acquired along evolution. This N-terminal tail appears to play a prominent role in the modulation of APE1 and probably in BER coordination. Thus, it is primarily involved in mediating APE1 localization, post-translational modifications, and protein–protein interactions, with all three factors jointly contributing to regulate the enzyme. In this review, recent insights on the regulatory role of the N-terminal region in several aspects of APE1 function are covered. In particular, interaction of this region with nucleophosmin (NPM1) might modulate certain APE1 activities, representing a paradigmatic example of the interconnection between various regulatory factors.

scholarly journals Stimulation of DNA Glycosylase Activities by XPC Protein Complex: Roles of Protein-Protein Interactions

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Yuichiro Shimizu ◽  
Yasuhiro Uchimura ◽  
Naoshi Dohmae ◽  
Hisato Saitoh ◽  
Fumio Hanaoka ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Abasic Site ◽  
Dna Glycosylases ◽  
Protein Protein Interactions ◽  
E Coli ◽  
Base Excision ◽  
Stimulation Of

We showed that XPC complex, which is a DNA damage detector for nucleotide excision repair, stimulates activity of thymine DNA glycosylase (TDG) that initiates base excision repair. XPC appeared to facilitate the enzymatic turnover of TDG by promoting displacement from its own product abasic site, although the precise mechanism underlying this stimulation has not been clarified. Here we show that XPC has only marginal effects on the activity ofE. coliTDG homolog (EcMUG), which remains bound to the abasic site like human TDG but does not significantly interacts with XPC. On the contrary, XPC significantly stimulates the activities of sumoylated TDG and SMUG1, both of which exhibit quite different enzymatic kinetics from unmodified TDG but interact with XPC. These results point to importance of physical interactions for stimulation of DNA glycosylases by XPC and have implications in the molecular mechanisms underlying mutagenesis and carcinogenesis in XP-C patients.

A new DNA breaks repair pathway involving PARP3 and base excision repair proteins

2018 ◽  
Vol 482 (1) ◽  
pp. 96-100
Author(s):  
E. Belousova ◽  
◽  
M. Kutuzov ◽  
P. Ivankina ◽  
A. Ishchenko ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathway ◽  
Dna Breaks ◽  
Base Excision

scholarly journals Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

2021 ◽  
Vol 22 (3) ◽  
pp. 1137
Author(s):  
Annalisa Ferino ◽  
Luigi E. Xodo
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Start Site ◽  
Dna Glycosylases ◽  
Repair Pathway ◽  
Transcription Start ◽  
G Quadruplex ◽  
Base Excision ◽  
Regulatory Functions

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.

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