Bacterial DNA repair genes and their eukaryotic homologues: 1. Mutations in genes involved in base excision repair (BER) and DNA-end processors and their implication in mutagenesis and human disease.

Base excision repair (BER) pathway executed by a complex network of proteins is the major system responsible for the removal of damaged DNA bases and repair of DNA single strand breaks (SSBs) generated by environmental agents, such as certain cancer therapies, or arising spontaneously during cellular metabolism. Both modified DNA bases and SSBs with ends other than 3'-OH and 5'-P are repaired either by replacement of a single or of more nucleotides in the processes called short-patch BER (SP-BER) or long-patch BER (LP-BER), respectively. In contrast to Escherichia coli cells, in human ones, the two BER sub-pathways are operated by different sets of proteins. In this review the selection between SP- and LP-BER and mutations in BER and end-processors genes and their contribution to bacterial mutagenesis and human diseases are considered.

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PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

10.1101/243071 ◽

2018 ◽

Author(s):

George E. Ronson ◽

Ann Liza Piberger ◽

Martin R. Higgs ◽

Anna L. Olsen ◽

Grant S. Stewart ◽

...

Keyword(s):

Base Excision Repair ◽

Damage Tolerance ◽

Excision Repair ◽

Replication Forks ◽

Strand Breaks ◽

Single Strand Breaks ◽

Dna Base ◽

Repair Mechanisms ◽

Base Excision

AbstractPARP1 regulates the repair of DNA single strand breaks (SSBs) generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whilst PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication associated DNA damage due to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and through stabilising replication forks that encounter BER intermediates.

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Accumulation of true single strand breaks and AP sites in base excision repair deficient cells

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/j.mrfmmm.2010.08.008 ◽

2010 ◽

Vol 694 (1-2) ◽

pp. 65-71 ◽

Cited By ~ 19

Author(s):

April M. Luke ◽

Paul D. Chastain ◽

Brian F. Pachkowski ◽

Valeriy Afonin ◽

Shunichi Takeda ◽

...

Keyword(s):

Base Excision Repair ◽

Excision Repair ◽

Single Strand ◽

Strand Breaks ◽

Single Strand Breaks ◽

Ap Sites ◽

Base Excision

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Base excision repair and its implications to cancer therapy

Essays in Biochemistry ◽

10.1042/ebc20200013 ◽

2020 ◽

Vol 64 (5) ◽

pp. 831-843 ◽

Cited By ~ 1

Author(s):

Gabrielle J. Grundy ◽

Jason L. Parsons

Keyword(s):

Oxidative Stress ◽

Cancer Cells ◽

Base Excision Repair ◽

Excision Repair ◽

Repair Process ◽

Loss Of Function ◽

Strand Breaks ◽

Single Strand Breaks ◽

Base Excision ◽

Integrity Of Dna

Abstract Base excision repair (BER) has evolved to preserve the integrity of DNA following cellular oxidative stress and in response to exogenous insults. The pathway is a coordinated, sequential process involving 30 proteins or more in which single strand breaks are generated as intermediates during the repair process. While deficiencies in BER activity can lead to high mutation rates and tumorigenesis, cancer cells often rely on increased BER activity to tolerate oxidative stress. Targeting BER has been an attractive strategy to overwhelm cancer cells with DNA damage, improve the efficacy of radiotherapy and/or chemotherapy, or form part of a lethal combination with a cancer specific mutation/loss of function. We provide an update on the progress of inhibitors to enzymes involved in BER, and some of the challenges faced with targeting the BER pathway.

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DNA breaks and chromosomal aberrations arise when replication meets base excision repair

The Journal of Cell Biology ◽

10.1083/jcb.201312078 ◽

2014 ◽

Vol 206 (1) ◽

pp. 29-43 ◽

Cited By ~ 65

Author(s):

Michael Ensminger ◽

Lucie Iloff ◽

Christian Ebel ◽

Teodora Nikolova ◽

Bernd Kaina ◽

...

Keyword(s):

Base Excision Repair ◽

Chromosomal Aberrations ◽

Excision Repair ◽

Double Strand Breaks ◽

Replication Forks ◽

Dna Double Strand Breaks ◽

Dna Breaks ◽

Strand Breaks ◽

Single Strand Breaks ◽

Base Excision

Exposures that methylate DNA potently induce DNA double-strand breaks (DSBs) and chromosomal aberrations, which are thought to arise when damaged bases block DNA replication. Here, we demonstrate that DNA methylation damage causes DSB formation when replication interferes with base excision repair (BER), the predominant pathway for repairing methylated bases. We show that cells defective in the N-methylpurine DNA glycosylase, which fail to remove N-methylpurines from DNA and do not initiate BER, display strongly reduced levels of methylation-induced DSBs and chromosomal aberrations compared with wild-type cells. Also, cells unable to generate single-strand breaks (SSBs) at apurinic/apyrimidinic sites do not form DSBs immediately after methylation damage. In contrast, cells deficient in x-ray cross-complementing protein 1, DNA polymerase β, or poly (ADP-ribose) polymerase 1 activity, all of which fail to seal SSBs induced at apurinic/apyrimidinic sites, exhibit strongly elevated levels of methylation-induced DSBs and chromosomal aberrations. We propose that DSBs and chromosomal aberrations after treatment with N-alkylators arise when replication forks collide with SSBs generated during BER.

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JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks

Nucleic Acids Research ◽

10.1093/nar/gkp054 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1936-1950 ◽

Cited By ~ 41

Author(s):

Shouyu Wang ◽

Zhenghua Gong ◽

Rui Chen ◽

Yunru Liu ◽

Aiping Li ◽

...

Keyword(s):

Oxidative Stress ◽

Base Excision Repair ◽

Excision Repair ◽

Single Strand ◽

Strand Breaks ◽

Single Strand Breaks ◽

Repair Protein ◽

Base Excision

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Uncoordinated long-patch base excision repair at juxtaposed DNA lesions generates a lethal accumulation of double-strand breaks

10.1101/2020.11.15.383513 ◽

2020 ◽

Author(s):

Kenji Shimada ◽

Barbara van Loon ◽

Christian B. Gerhold ◽

Stephanie Bregenhorn ◽

Verena Hurst ◽

...

Keyword(s):

Base Excision Repair ◽

Excision Repair ◽

Dna Lesions ◽

Double Strand Breaks ◽

Yeast Genome ◽

Dsb Repair ◽

Strand Breaks ◽

Tor Pathway ◽

Modified Dna ◽

Base Excision

SummaryInhibition of the TOR pathway (TORC2, or Ypk1/2), or the depolymerization of actin filaments results in catastrophic fragmentation of the yeast genome upon exposure to low doses of the radiomimetic drug Zeocin. We find that the accumulation of double-strand breaks (DSB) is not due to altered DSB repair, but by the uncoordinated activity of base excision repair (BER) at Zeocin-modified DNA bases. We inhibit DSB formation by eliminating glycosylases and/or the endonucleases Apn1/2 and Rad1, implicating these conserved BER enzymes, or events downstream of them, in the conversion of base damage into DSBs. Among DNA polymerases, the reduction of Pol δ, and to a lesser extent Pol ε and Trf4 (a Pol β-like polymerase), reduces DSB formation. Finally, the BER enzymes, Ogg1 and AP endonuclease, are shown to co-precipitate with actin from yeast extracts and as purified proteins, suggesting that actin may interfere directly with the repair of Zeocin-induced damage.

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

International Journal of Molecular Sciences ◽

10.3390/ijms23020893 ◽

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.

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