8-Oxoguanine DNA glycosylase (Ogg1) causes a transcriptional inactivation of damaged DNA in the absence of functional Cockayne syndrome B (Csb) protein

Khobta, Andriy; Kitsera, Nataliya; Speckmann, Bodo; Epe, Bernd

doi:10.1016/j.dnarep.2008.11.006

Cited by 37 publications

(49 citation statements)

References 28 publications

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“…While we make the simplifying assumption that the resulting AP site is directly responsible for the observed TC-NER, a protein-bound AP site may be the relevant block in some or all cases. We suggest that the transcription-coupled repair of glycosylase-generated AP sites is likely a conserved mechanism that links BER to TC-NER in a wide variety of systems (7,28).…”

Section: Discussionmentioning

confidence: 99%

Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

Kim

Jinks-Robertson

2010

Molecular and Cellular Biology

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Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.High levels of transcription affect genome stability by stimulating mutagenesis and homologous recombination, both of which are well-known consequences of DNA damage (for reviews, see references 2 and 3). Consistently with a link between transcription and DNA damage accumulation, highly transcribed sequences in the yeast Saccharomyces cerevisiae are more susceptible to exogenous mutagens (19), and spontaneous transcription-associated mutagenesis (TAM) is further elevated when DNA repair is compromised (11,30,38). While there likely are multiple causes for and types of damage that accumulate in transcriptionally active DNA, we recently demonstrated that apurinic/apyrimidinic (AP) sites can be a significant source of TAM (30). AP sites are one of the most common DNA lesions and can be a potent block to replicative DNA polymerases (reviewed in reference 15). Blocked DNA synthesis can be rescued either by a recombination/template switch mechanism or through the recruitment of specialized translesion synthesis (TLS) DNA polymerases (14). In yeast, TLS polymerase (Pol), together with the deoxycytidyl transferase Rev1, is required for most AP-site bypass, with a C nucleotide usually being inserted across from the template lesion (20,31,39). Depending on the base lost, AP-site bypass via TLS has the potential to be highly mutagenic.AP sites can be generated by the spontaneous hydrolysis of the sugar base glycosidic linkage or are formed when a specialized DNA N-glycosylase releases its cognate damaged base from the sugar phosphate backbone (reviewed in references 6 and 15). In yeast, genetic studies have demonstrated that most spontaneous AP sites originate from the incorporation of dUTP in place of dTTP during DNA synthesis (22). Subsequent uracil removal by Ung1, the sole uracil DNA glycosylase in S. cerevisiae, creates a potentially toxic/mutagenic AP site. As a part of the cellular defense mechanism against uracil incorporation into DNA, dUTPase, an essential enzyme in yeast (16) as well as in Escherichia coli (13), catalyzes the conversion of dUTP to dUMP. ...

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Section: Discussionmentioning

confidence: 99%

Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

Kim

Jinks-Robertson

2010

Molecular and Cellular Biology

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“…The interaction of CSB with APE1 stimulates incision of the DNA backbone by APE1 in a manner dependent on ATP (Wong et al, 2007). When functional CSB is absent the processing of 8-oxo-dG base modifications by the DNA glycosylase OGG1 appears to cause a strong transcriptional inactivation of the damaged gene (Khobta et al, 2009). Additional OGG1 deficiency can attenuate this effect making it likely that the SSB and AP site repair intermediates generated by OGG1 are the reason for gene inactivation.…”

Section: Base Excision Repair Deficiencymentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

299

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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“…However, the notion that CS factors and in particular CSB are implicated in the response to oxidative DNA damage (Stevnsner et al 2008) has been debated over the years, with sometimes conflicting data and models, ranging from reduced incision activity on an 8-oxo-G DNA substrate (Dianov et al 1999) to the absence of this (Osterod et al 2002), or implicating CSB in global genome base excision repair (BER) function by affecting the expression of the BER glycosylase OGG1 . Also, whether 8-oxo-G lesions affect RNAPII elongation has been disputed by conflicting results, ranging from weak transcriptional interference to complete absence of an effect (Tornaletti et al 2004;Charlet-Berguerand et al 2006;Spivak and Hanawalt 2006;Khobta et al 2009). Very recently, however, with the aid of the development of a novel laser-directed method to locally inflict oxidative DNA damage in living cells, a clear transcription-coupled recruitment of CSB to these lesions was observed (Menoni et al 2012).…”

Section: Transcription-dependent Genome Surveillancementioning

confidence: 99%

Mammalian Transcription-Coupled Excision Repair

Vermeulen¹,

Fousteri

2013

Cold Spring Harbor Perspectives in Biology

157

118

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Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.

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8-Oxoguanine DNA glycosylase (Ogg1) causes a transcriptional inactivation of damaged DNA in the absence of functional Cockayne syndrome B (Csb) protein

Cited by 37 publications

References 28 publications

Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

DNA repair deficiency in neurodegeneration

Mammalian Transcription-Coupled Excision Repair

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