Base Excision Repair in Physiology and Pathology of the Central Nervous System

Bosshard, Matthias; Markkanen, Enni; Loon, Barbara van

doi:10.3390/ijms131216172

Cited by 24 publications

(27 citation statements)

References 294 publications

(332 reference statements)

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“…This is consistent with accumulating evidence that DNA repair pathways and other components of the DNA damage response play a role in preventing neuropathology (Fishel et al 2007; Rulten and Caldecott 2013; Madabhushi et al 2014). Oxidative damage to neuronal cells may be an important component of neurodegeneration, as suggested by reports that BER is important in preventing neurodegeneration (Liu et al 2011; Bosshard et al 2012; Sheng et al 2012; Canugovi et al 2013; Lillenes et al 2013). The mammalian brain consumes oxygen at a relatively high rate, leading to high exposure of neurons to the associated ROS by-products; if antioxidants are depleted in the brain, neurons become susceptible to ROS-induced DNA damage (Sai et al 1992; Hirano et al 1996; Kaneko et al 1996; Nakae et al 2000; Barja 2004).…”

Section: Neurodegenerative Disease and Premature Agingmentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

334

197

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Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

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Section: Neurodegenerative Disease and Premature Agingmentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

334

197

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“…The role of single-strand breaks generated by MUTYH in the induction of cell death was further underlined by the finding that synthetic sickness/lethality mediated by either inhibition of pol β combined with MSH2, a component of the mismatch repair pathway, or pol γ with MLH1, both of which led to a nuclear 8-oxo-G accumulation, could be rescued by silencing of MUTYH (Martin et al, 2010). BER has been implicated in many different pathological conditions of the central nervous system (reviewed in Bosshard et al, 2012). A very recent report implicated MUTYH in degeneration by triggering apoptosis in microglia and neurons through initiation of single-strand breaks during repair of A:8-oxo-G mismatches (Sheng et al, 2012).…”

Section: Function Of Muty and Mutyhmentioning

confidence: 99%

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

Markkanen¹,

Dorn²,

Hübscher³

2013

Front. Genet.

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Maintenance of genetic stability is crucial for all organisms in order to avoid the onset of deleterious diseases such as cancer. One of the many proveniences of DNA base damage in mammalian cells is oxidative stress, arising from a variety of endogenous and exogenous sources, generating highly mutagenic oxidative DNA lesions. One of the best characterized oxidative DNA lesion is 7,8-dihydro-8-oxoguanine (8-oxo-G), which can give rise to base substitution mutations (also known as point mutations). This mutagenicity is due to the miscoding potential of 8-oxo-G that instructs most DNA polymerases (pols) to preferentially insert an Adenine (A) opposite 8-oxo-G instead of the appropriate Cytosine (C). If left unrepaired, such A:8-oxo-G mispairs can give rise to CG→AT transversion mutations. A:8-oxo-G mispairs are proficiently recognized by the MutY glycosylase homologue (MUTYH). MUTYH can remove the mispaired A from an A:8-oxo-G, giving way to the canonical base-excision repair (BER) that ultimately restores undamaged Guanine (G). The importance of this MUTYH-initiated pathway is illustrated by the fact that biallelic mutations in the MUTYH gene are associated with a hereditary colorectal cancer syndrome termed MUTYH-associated polyposis (MAP). In this review, we will focus on MUTYH, from its discovery to the most recent data regarding its cellular roles and interaction partners. We discuss the involvement of the MUTYH protein in the A:8-oxo-G BER pathway acting together with pol λ, the pol that can faithfully incorporate C opposite 8-oxo-G and thus bypass this lesion in a correct manner. We also outline the current knowledge about the regulation of MUTYH itself and the A:8-oxo-G repair pathway by posttranslational modifications (PTM). Finally, to achieve a clearer overview of the literature, we will briefly touch on the rather confusing MUTYH nomenclature. In short, MUTYH is a unique DNA glycosylase that catalyzes the excision of an undamaged base from DNA.

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“…Interestingly, recent work in mice focusing on DNA glycosylases responsible for the repair of oxidized bases, similarly, suggested the role of glycosylases in regulation of ERα-gene expression 20 . Taken together, these findings indicate that coupling of AAG-initiated BER to 4 transcription could enable more efficient repair and that AAG potentially influences gene expression.…”

Section: Introductionmentioning

confidence: 74%

“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

Montaldo¹,

Bordin²,

Brambilla³

et al. 2019

Preprint

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Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG; aka MPG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms complex with active RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation.Importantly, at co-regulated genes aberrantly methylated bases accumulate towards 3'end, in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide novel insights to maintaining genome stability in actively transcribing chromatin, and reveal roles of aberrantly methylated bases in regulation of gene expression.

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Base Excision Repair in Physiology and Pathology of the Central Nervous System

Cited by 24 publications

References 294 publications

DNA Damage, DNA Repair, Aging, and Neurodegeneration

DNA Damage, DNA Repair, Aging, and Neurodegeneration

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

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