scholarly journals XRCC1 Prevents Replication Fork Instability during Misincorporation of the DNA Demethylation Bases 5-Hydroxymethyl-2′-Deoxycytidine and 5-Hydroxymethyl-2′-Deoxyuridine

2022 ◽  
Vol 23 (2) ◽  
pp. 893
Author(s):  
María José Peña-Gómez ◽  
Marina Suárez-Pizarro ◽  
Iván V. Rosado
Keyword(s):  
Genomic Instability ◽  
Base Excision Repair ◽  
Replication Fork ◽  
Genome Stability ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Dna Bases ◽  
Stem Cell Pluripotency ◽  
Base Excision

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well characterized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2′-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2′-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1−/− cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1.

Decrease in Abundance of Apurinic/Apyrimidinic Endonuclease Causes Failure of Base Excision Repair in Culture-Adapted Human Embryonic Stem Cells

Stem Cells ◽  
2013 ◽  
Vol 31 (4) ◽  
pp. 693-702 ◽  
Author(s):  
Miriama Krutá ◽  
Lukáš Bálek ◽  
Renata Hejnová ◽  
Zuzana Dobšáková ◽  
Livia Eiselleová ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Base Excision Repair ◽  
Human Embryonic Stem Cells ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Base Excision

scholarly journals Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins

2014 ◽  
Vol 25 (10) ◽  
pp. 1641-1652 ◽  
Author(s):  
Mattia Poletto ◽  
Lisa Lirussi ◽  
David M. Wilson ◽  
Gianluca Tell
Keyword(s):  
Dna Damage Response ◽  
Base Excision Repair ◽  
Genome Stability ◽  
Excision Repair ◽  
Multifunctional Protein ◽  
Protein Levels ◽  
Exact Function ◽  
Damage Response ◽  
Base Excision ◽  
Representative Protein

Nucleophosmin (NPM1) is a multifunctional protein that controls cell growth and genome stability via a mechanism that involves nucleolar–cytoplasmic shuttling. It is clear that NPM1 also contributes to the DNA damage response, yet its exact function is poorly understood. We recently linked NPM1 expression to the functional activation of the major abasic endonuclease in mammalian base excision repair (BER), apurinic/apyrimidinic endonuclease 1 (APE1). Here we unveil a novel role for NPM1 as a modulator of the whole BER pathway by 1) controlling BER protein levels, 2) regulating total BER capacity, and 3) modulating the nucleolar localization of several BER enzymes. We find that cell treatment with the genotoxin cisplatin leads to concurrent relocalization of NPM1 and BER components from nucleoli to the nucleoplasm, and cellular experiments targeting APE1 suggest a role for the redistribution of nucleolar BER factors in determining cisplatin toxicity. Finally, based on the use of APE1 as a representative protein of the BER pathway, our data suggest a function for BER proteins in the regulation of ribogenesis.

scholarly journals Direct and Base Excision Repair-Mediated Regulation of a GC-Rich cis-Element in Response to 5-Formylcytosine and 5-Carboxycytosine

2021 ◽  
Vol 22 (20) ◽  
pp. 11025
Author(s):  
Nadine Müller ◽  
Eveliina Ponkkonen ◽  
Thomas Carell ◽  
Andriy Khobta
Keyword(s):  
Rna Polymerase Ii ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Core Promoter ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Promoter Activation ◽  
Cis Element ◽  
Base Excision ◽  
Cg Dinucleotide

Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2′-deoxy-(5-fC/5-caC) or their BER-resistant 2′-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5′-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5′-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches.

scholarly journals Mismatch and base excision repair proficiency in murine embryonic stem cells

DNA Repair ◽  
2011 ◽  
Vol 10 (4) ◽  
pp. 445-451 ◽  
Author(s):  
Elisia D. Tichy ◽  
Li Liang ◽  
Li Deng ◽  
Jay Tischfield ◽  
Sandy Schwemberger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Murine Embryonic Stem Cells ◽  
Base Excision
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