scholarly journals The Transition of Closely Opposed Lesions to Double-Strand Breaks during Long-Patch Base Excision Repair Is Prevented by the Coordinated Action of DNA Polymerase δ and Rad27/Fen1

2008 ◽  
Vol 29 (5) ◽  
pp. 1212-1221 ◽  
Author(s):  
Wenjian Ma ◽  
Vijayalakshmi Panduri ◽  
Joan F. Sterling ◽  
Bennett Van Houten ◽  
Dmitry A. Gordenin ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Single Strand ◽  
S1 Nuclease ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Dna Polymerase Δ ◽  
Base Excision

ABSTRACT DNA double-strand breaks can result from closely opposed breaks induced directly in complementary strands. Alternatively, double-strand breaks could be generated during repair of clustered damage, where the repair of closely opposed lesions has to be well coordinated. Using single and multiple mutants of Saccharomyces cerevisiae (budding yeast) that impede the interaction of DNA polymerase δ and the 5′-flap endonuclease Rad27/Fen1 with the PCNA sliding clamp, we show that the lack of coordination between these components during long-patch base excision repair of alkylation damage can result in many double-strand breaks within the chromosomes of nondividing haploid cells. This contrasts with the efficient repair of nonclustered methyl methanesulfonate-induced lesions, as measured by quantitative PCR and S1 nuclease cleavage of single-strand break sites. We conclude that closely opposed single-strand lesions are a unique threat to the genome and that repair of closely opposed strand damage requires greater spatial and temporal coordination between the participating proteins than does widely spaced damage in order to prevent the development of double-strand breaks.

scholarly journals Distinct spatiotemporal patterns and PARP dependence of XRCC1 recruitment to single-strand break and base excision repair

2013 ◽  
Vol 41 (5) ◽  
pp. 3115-3129 ◽  
Author(s):  
Anna Campalans ◽  
Thierry Kortulewski ◽  
Rachel Amouroux ◽  
Hervé Menoni ◽  
Wim Vermeulen ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Spatiotemporal Patterns ◽  
Single Strand Break ◽  
Base Excision

scholarly journals XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair

2021 ◽  
Author(s):  
Marek Adamowicz ◽  
Richard Hailstone ◽  
Annie A. Demin ◽  
Emilia Komulainen ◽  
Hana Hanzlikova ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Neurological Disease ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Toxic Activity ◽  
Single Strand Break ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

AbstractGenetic defects in the repair of DNA single-strand breaks (SSBs) can result in neurological disease triggered by toxic activity of the single-strand-break sensor protein PARP1. However, the mechanism(s) by which this toxic PARP1 activity triggers cellular dysfunction are unclear. Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1−/− mouse neurons. This defect is caused by excessive/aberrant PARP1 activity during DNA base excision repair, resulting from the loss of PARP1 regulation by XRCC1. We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation. Importantly, inhibition and/or deletion of PARP1 or USP3 restores transcriptional recovery in XRCC1−/− cells, highlighting PARP1 and USP3 as possible therapeutic targets in neurological disease.

scholarly journals Nonhomologous end joining of complex DNA double-strand breaks with proximal thymine glycol and interplay with base excision repair

DNA Repair ◽  
2016 ◽  
Vol 41 ◽  
pp. 16-26 ◽  
Author(s):  
Mohammed Almohaini ◽  
Sri Lakshmi Chalasani ◽  
Duaa Bafail ◽  
Konstantin Akopiants ◽  
Tong Zhou ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Thymine Glycol ◽  
Base Excision

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

2010 ◽  
Vol 694 (1-2) ◽  
pp. 65-71 ◽  
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

scholarly journals Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

2015 ◽  
Vol 35 (9) ◽  
pp. 1648-1658 ◽  
Author(s):  
Anna Campalans ◽  
Eva Moritz ◽  
Thierry Kortulewski ◽  
Denis Biard ◽  
Bernd Epe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Main Function ◽  
Single Strand Break ◽  
Single Strand Break Repair ◽  
Base Excision ◽  
Epidemiology Studies

XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies.

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

2014 ◽  
Vol 206 (1) ◽  
pp. 29-43 ◽  
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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