Oxygen as a friend and enemy: How to combat the mutational potential of 8-oxo-guanine

Loon, Barbara van; Markkanen, Enni; Hübscher, Ulrich

doi:10.1016/j.dnarep.2010.03.004

Cited by 284 publications

(242 citation statements)

References 182 publications

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“…The most extensively studied glycosylase is OGG1. It is responsible for excising 8-oxo-guanine, a common base damage caused by reactive oxygen species (53). In cell extracts and in mice, it has been shown that OGG1 normally acts to promote CAG repeat expansions (21,33).…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately highthroughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phosphodiesterase 1 (TDP1), and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions. The TOP1-TDP1-SSBR pathway normally functions to suppress repeat instability, since interfering with it stimulated repeat contractions. We further showed that the increase in repeat contractions when the TOP1-TDP1-SSBR pathway is compromised arises via transcription-coupled nucleotide excision repair, a previously identified contributor to transcription-induced repeat instability. These studies broaden the scope of pathways involved in transcription-induced CAG repeat instability and begin to define their interrelationships.

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Section: Discussionmentioning

confidence: 99%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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“…In contact with DNA, ROS generates base damage, such as 7,8-dihydro-8-oxo-guanine (8-oxo-G), which, if not repaired, increases the chance of mispairing adenine opposite the lesion. 38 ROS may also lead to breaks in the phosphodiester chain of DNA, including double-strand breaks (DSBs) that are normally detected by g-H2AX. 39 These extremely toxic and deleterious lesions may cause chromosome alterations or even cell death.…”

Section: Autophagy Mitochondria Metabolism and Tumorigenesismentioning

confidence: 99%

Autophagy and genomic integrity

et al. 2013

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DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.

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“…MutYH, a known interactor of Pol λ (7), recognizes 8-oxo-G:A mismatches and catalyzes the excision of the wrong A (reviewed in ref. 2). This step is followed by incision of the apurinic/apyrimidinic (AP) site by the action of apurinic/apyrimidinic endonuclease 1 (Ape1) to generate the substrate for Pol that performs the subsequent gap filling reaction (25).…”

Section: Phosphorylation Of Dna Polymerase λ Enhances Its Interactionmentioning

confidence: 99%

“…Because of its prevalence and high mutagenic potential, 8-oxo-2′-deoxyguanine (8-oxo-G) is recognized as one of the most abundant mutagenic oxidative DNA lesions arising from such insults (reviewed in ref. 2). The cardinal problem with 8-oxo-G is that the majority of polymerases (Pols), including the three replicative Pols α, δ, and ϵ, bypass 8-oxo-G in an inaccurate manner by frequently incorporating the "wrong" adenine (A) opposite 8-oxo-G.…”

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confidence: 99%

Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by cross-talk of phosphorylation and ubiquitination

Markkanen

Loon

Ferrari

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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It is of pivotal importance for genome stability that repair DNA polymerases (Pols), such as Pols λ and β, which all exhibit considerably reduced fidelity when replicating undamaged DNA, are tightly regulated, because their misregulation could lead to mutagenesis. Recently, we found that the correct repair of the abundant and highly miscoding oxidative DNA lesion 7,8-dihydro-8-oxo-2′-deoxyguanine (8-oxo-G) is performed by an accurate repair pathway that is coordinated by the MutY glycosylase homologue (MutYH) and Pol λ in vitro and in vivo. Pol λ is phosphorylated by Cdk2/cyclinA in late S and G2 phases of the cell cycle, promoting Pol λ stability by preventing it from being targeted for proteasomal degradation by ubiquitination. However, it has remained a mystery how the levels of Pol λ are controlled, how phosphorylation promotes its stability, and how the engagement of Pol λ in active repair complexes is coordinated. Here, we show that the E3 ligase Mule mediates the degradation of Pol λ and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. Furthermore, we demonstrate that phosphorylation of Pol λ by Cdk2/cyclinA counteracts its Mule-mediated degradation by promoting recruitment of Pol λ to chromatin into active 8-oxo-G repair complexes through an increase in Pol λ’s affinity to chromatin-bound MutYH. Finally, MutYH appears to promote the stability of Pol λ by binding it to chromatin. In contrast, Pol λ not engaged in active repair on chromatin is subject for proteasomal degradation.

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Oxygen as a friend and enemy: How to combat the mutational potential of 8-oxo-guanine

Cited by 284 publications

References 182 publications

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Autophagy and genomic integrity

Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by cross-talk of phosphorylation and ubiquitination

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