scholarly journals An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation

2016 ◽  
Vol 44 (8) ◽  
pp. 3713-3727 ◽  
Author(s):  
Inga Grin ◽  
Alexander A. Ishchenko
Keyword(s):  
Mismatch Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Active Dna Demethylation ◽  
Repair Pathways ◽  
Base Excision

scholarly journals Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity

2013 ◽  
Vol 41 (15) ◽  
pp. 7332-7343 ◽  
Author(s):  
Anbarasi Kothandapani ◽  
Akshada Sawant ◽  
Venkata Srinivas Mohan Nimai Dangeti ◽  
Robert W. Sobol ◽  
Steve M. Patrick
Keyword(s):  
Mismatch Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Pathways ◽  
Base Excision

scholarly journals Thymine DNA Glycosylase Is Essential for Active DNA Demethylation by Linked Deamination-Base Excision Repair

Cell ◽  
2011 ◽  
Vol 146 (1) ◽  
pp. 67-79 ◽  
Author(s):  
Salvatore Cortellino ◽  
Jinfei Xu ◽  
Mara Sannai ◽  
Robert Moore ◽  
Elena Caretti ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Active Dna Demethylation ◽  
Base Excision

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.

scholarly journals Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine

2011 ◽  
Vol 286 (41) ◽  
pp. 35334-35338 ◽  
Author(s):  
Atanu Maiti ◽  
Alexander C. Drohat
Keyword(s):  
Embryonic Development ◽  
Catalytic Mechanism ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Oxidation Products ◽  
Dna Glycosylase ◽  
Thymine Dna Glycosylase ◽  
Active Demethylation ◽  
Active Dna Demethylation ◽  
Base Excision

Thymine DNA glycosylase (TDG) excises T from G·T mispairs and is thought to initiate base excision repair (BER) of deaminated 5-methylcytosine (mC). Recent studies show that TDG, including its glycosylase activity, is essential for active DNA demethylation and embryonic development. These and other findings suggest that active demethylation could involve mC deamination by a deaminase, giving a G·T mispair followed by TDG-initiated BER. An alternative proposal is that demethylation could involve iterative oxidation of mC to 5-hydroxymethylcytosine (hmC) and then to 5-formylcytosine (fC) and 5-carboxylcytosine (caC), mediated by a Tet (ten eleven translocation) enzyme, with conversion of caC to C by a putative decarboxylase. Our previous studies suggest that TDG could excise fC and caC from DNA, which could provide another potential demethylation mechanism. We show here that TDG rapidly removes fC, with higher activity than for G·T mispairs, and has substantial caC excision activity, yet it cannot remove hmC. TDG excision of fC and caC, oxidation products of mC, is consistent with its strong specificity for excising bases from a CpG context. Our findings reveal a remarkable new aspect of specificity for TDG, inform its catalytic mechanism, and suggest that TDG could protect against fC-induced mutagenesis. The results also suggest a new potential mechanism for active DNA demethylation, involving TDG excision of Tet-produced fC (or caC) and subsequent BER. Such a mechanism obviates the need for a decarboxylase and is consistent with findings that TDG glycosylase activity is essential for active demethylation and embryonic development, as are mechanisms involving TDG excision of deaminated mC or hmC.

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