Editing Reactive oxygen species (section)

==Positive role of ROS in memory==

[[File:Initiation of DNA demethylation at a CpG site.svg|thumb|400 px|Initiation of [[DNA demethylation]] at a [[CpG site]]. In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides ([[CpG sites]]), forming [[5-methylcytosine]]-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming [[8-oxo-2'-deoxyguanosine|8-hydroxy-2'-deoxyguanosine]] (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site.  The [[base excision repair]] enzyme [[oxoguanine glycosylase|OGG1]] targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits [[Tet methylcytosine dioxygenase 1|TET1]] and TET1 oxidizes the 5mC adjacent to the 8-OHdG.  This initiates demethylation of 5mC.<ref name="Zhou">{{Cite journal |display-authors=6 |vauthors=Zhou X, Zhuang Z, Wang W, He L, Wu H, Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo Z |date=September 2016 |title=OGG1 is essential in oxidative stress induced DNA demethylation |journal=Cellular Signalling |volume=28 |issue=9 |pages=1163–1171 |doi=10.1016/j.cellsig.2016.05.021 |pmid=27251462}}</ref>]]

[[File:Demethylation of 5-methylcytosine.svg|thumb|400 px|Demethylation of [[5-Methylcytosine]] (5mC) in neuron DNA.  As reviewed in 2018,<ref name="pmid29875631">{{Cite journal |vauthors=Bayraktar G, Kreutz MR |date=2018 |title=The Role of Activity-Dependent DNA Demethylation in the Adult Brain and in Neurological Disorders |journal=Frontiers in Molecular Neuroscience |volume=11 |pages=169 |doi=10.3389/fnmol.2018.00169 |pmc=5975432 |pmid=29875631 |doi-access=free}}</ref> in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases ([[Tet methylcytosine dioxygenase 1|TET1]], [[Tet methylcytosine dioxygenase 2|TET2]], [[Tet methylcytosine dioxygenase 3|TET3]]) to generate [[5-hydroxymethylcytosine]] (5hmC).  In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). [[Thymine-DNA glycosylase]] (TDG) recognizes the intermediate bases 5fC and 5caC and excises the [[glycosidic bond]] resulting in an apyrimidinic site ([[AP site]]).  In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex [[APOBEC3G|(AID/APOBEC)]] deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to [[thymine]] (Thy).  5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 ([[SMUG1]]), Nei-Like DNA Glycosylase 1 ([[NEIL1]]), or methyl-CpG binding protein 4 ([[MBD4]]).  AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield [[cytosine]] (Cyt).]]

ROS are critical in [[memory]] formation.<ref name="pmid20649473">{{Cite journal |vauthors=Massaad CA, Klann E |date=May 2011 |title=Reactive oxygen species in the regulation of synaptic plasticity and memory |journal=Antioxidants & Redox Signaling |volume=14 |issue=10 |pages=2013–2054 |doi=10.1089/ars.2010.3208 |pmc=3078504 |pmid=20649473}}</ref><ref name="pmid27625575">{{Cite journal |vauthors=Beckhauser TF, Francis-Oliveira J, De Pasquale R |date=2016 |title=Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity |journal=Journal of Experimental Neuroscience |volume=10 |issue=Suppl 1 |pages=23–48 |doi=10.4137/JEN.S39887 |pmc=5012454 |pmid=27625575}}</ref><ref>{{Cite journal |last1=Rabah |first1=Yasmine |last2=Berwick |first2=Jean-Paul |last3=Sagar |first3=Nisrine |last4=Pasquer |first4=Laure |last5=Plaçais |first5=Pierre-Yves |last6=Preat |first6=Thomas |date=February 2025|title=Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer's disease model |journal=Nature Metabolism |language=en |volume=7 |issue=2 |pages=321–335 |doi=10.1038/s42255-024-01189-3 |issn=2522-5812 |pmc=11860231 |pmid=39856222}}</ref> ROS also have a central role in epigenetic [[DNA demethylation]], which is relevant to [[Epigenetics in learning and memory|learning and memory]]<ref name="pmid21116250">{{Cite journal |vauthors=Day JJ, Sweatt JD |date=January 2011 |title=Epigenetic modifications in neurons are essential for formation and storage of behavioral memory |journal=Neuropsychopharmacology |volume=36 |issue=1 |pages=357–358 |doi=10.1038/npp.2010.125 |pmc=3055499 |pmid=21116250}}</ref><ref name="pmid26875778">{{Cite journal |vauthors=Sweatt JD |date=October 2016 |title=Neural plasticity and behavior - sixty years of conceptual advances |journal=Journal of Neurochemistry |volume=139 |issue=Suppl 2 |pages=179–199 |doi=10.1111/jnc.13580 |pmid=26875778 |doi-access=free}}</ref>

In mammalian nuclear DNA, a methyl group can be added, by a [[DNA methyltransferase]], to the 5th carbon of cytosine to form 5mC (see red methyl group added to form 5mC near the top of the first figure).  The DNA methyltransferases most often form 5mC within the dinucleotide sequence "cytosine-phosphate-guanine" to form 5mCpG.  This addition is a major type of epigenetic alteration and it can [[Regulation of gene expression#Chemical|silence gene expression]].  Methylated cytosine can also be [[DNA demethylation|demethylated]], an epigenetic alteration that can increase the expression of a gene.  A major enzyme involved in demethylating 5mCpG is [[Tet methylcytosine dioxygenase 1|TET1]].  However, TET1 is only able to act on 5mCpG if an ROS has first acted on the guanine to form [[8-oxo-2'-deoxyguanosine|8-hydroxy-2'-deoxyguanosine]] (8-OHdG), resulting in a 5mCp-8-OHdG dinucleotide .<ref name="Zhou" />  However, TET1 is only able to act on the 5mC part of the dinucleotide when the [[base excision repair]] enzyme [[oxoguanine glycosylase|OGG1]] binds to the 8-OHdG lesion without immediate excision. Adherence of OGG1 to the 5mCp-8-OHdG site recruits [[Tet methylcytosine dioxygenase 1|TET1]] and TET1 then oxidizes the 5mC adjacent to 8-OHdG, as shown in the first figure, initiating a demethylation pathway shown in the second figure.

The thousands of CpG sites being demethylated during memory formation depend on ROS in an initial step.  The altered protein expression in neurons, controlled in part by ROS-dependent demethylation of CpG sites in gene promoters within neuron DNA, are central to memory formation.<ref name="pmid20975755">{{Cite journal |vauthors=Day JJ, Sweatt JD |date=November 2010 |title=DNA methylation and memory formation |journal=Nature Neuroscience |volume=13 |issue=11 |pages=1319–1323 |doi=10.1038/nn.2666 |pmc=3130618 |pmid=20975755}}</ref>