Editing DNA (section)

== Chemical modifications and altered DNA packaging ==

=== Base modifications and DNA packaging ===
{{further|DNA methylation|Chromatin remodeling}}
<div class="thumb tright" style="background:#f9f9f9; border:1px solid #ccc; margin:0.5em;">
{| border="0" cellpadding="2" cellspacing="0" style="width:300px; font-size:85%; border:1px solid #ccc; margin:0.3em;"
|-
|[[File:Cytosin.svg|75px]]
|[[File:5-Methylcytosine.svg|95px]]
|[[File:Thymin.svg|97px]]
|-
|align=center|[[cytosine]]
|align=center|[[5-Methylcytosine|5-methylcytosine]]
|align=center|[[thymine]]
|}
<div style="border: none; width:300px;font-size: 90%;"><div class="thumbcaption">Structure of cytosine with and without the 5-methyl group. [[Deamination]] converts 5-methylcytosine into thymine.</div></div></div>
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called [[chromatin]]. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of [[methylation]] of [[cytosine]] bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the [[histone]] protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see [[Chromatin remodeling]]). There is, further, [[Crosstalk (biology)|crosstalk]] between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.<ref>{{cite journal | vauthors = Hu Q, Rosenfeld MG | title = Epigenetic regulation of human embryonic stem cells | journal = Frontiers in Genetics | volume = 3 | pages = 238 | year = 2012 | pmid = 23133442 | pmc = 3488762 | doi = 10.3389/fgene.2012.00238 | doi-access = free }}</ref>

For one example, cytosine methylation produces [[5-Methylcytosine|5-methylcytosine]], which is important for [[X-inactivation]] of chromosomes.<ref>{{cite journal | vauthors = Klose RJ, Bird AP | title = Genomic DNA methylation: the mark and its mediators | journal = Trends in Biochemical Sciences | volume = 31 | issue = 2 | pages = 89–97 | date = February 2006 | pmid = 16403636 | doi = 10.1016/j.tibs.2005.12.008 }}</ref> The average level of methylation varies between organisms—the worm ''[[Caenorhabditis elegans]]'' lacks cytosine methylation, while [[vertebrate]]s have higher levels, with up to 1% of their DNA containing 5-methylcytosine.<ref>{{cite journal | vauthors = Bird A | title = DNA methylation patterns and epigenetic memory | journal = Genes & Development | volume = 16 | issue = 1 | pages = 6–21 | date = January 2002 | pmid = 11782440 | doi = 10.1101/gad.947102 | doi-access = free }}</ref> Despite the importance of 5-methylcytosine, it can [[deamination|deaminate]] to leave a thymine base, so methylated cytosines are particularly prone to [[mutation]]s.<ref>{{cite book | vauthors = Walsh CP, Xu GL | title = DNA Methylation: Basic Mechanisms | chapter = Cytosine methylation and DNA repair | volume = 301 | pages = 283–315 | year = 2006 | pmid = 16570853 | doi = 10.1007/3-540-31390-7_11 | isbn = 3-540-29114-8 | series = Current Topics in Microbiology and Immunology }}</ref> Other base modifications include adenine methylation in bacteria, the presence of [[5-hydroxymethylcytosine]] in the [[brain]],<ref>{{cite journal | vauthors = Kriaucionis S, Heintz N | title = The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain | journal = Science | volume = 324 | issue = 5929 | pages = 929–30 | date = May 2009 | pmid = 19372393 | pmc = 3263819 | doi = 10.1126/science.1169786 | bibcode = 2009Sci...324..929K }}</ref> and the [[glycosylation]] of uracil to produce the "J-base" in [[Kinetoplastida|kinetoplastids]].<ref>{{cite journal | vauthors = Ratel D, Ravanat JL, Berger F, Wion D | title = N6-methyladenine: the other methylated base of DNA | journal = BioEssays | volume = 28 | issue = 3 | pages = 309–15 | date = March 2006 | pmid = 16479578 | pmc = 2754416 | doi = 10.1002/bies.20342 }}</ref><ref>{{cite journal | vauthors = Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA, Crain PF, Borst P | s2cid = 24801094 | title = beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei | journal = Cell | volume = 75 | issue = 6 | pages = 1129–36 | date = December 1993 | pmid = 8261512 | doi = 10.1016/0092-8674(93)90322-H | hdl = 1874/5219 | hdl-access = free }}</ref>

=== Damage ===
{{further|DNA damage (naturally occurring)|Mutation|DNA damage theory of aging}}
[[File:Benzopyrene DNA adduct 1JDG.png|thumb|right|A [[covalent]] [[adduct]] between a [[Cytochrome P450, family 1, member A1|metabolically activated]] form of [[Benzo(a)pyrene|benzo[''a'']pyrene]], the major [[mutagen]] in [[tobacco smoking|tobacco smoke]], and DNA<ref>Created from [http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG PDB 1JDG] {{Webarchive|url=https://web.archive.org/web/20080922150848/http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1JDG |date=22 September 2008 }}</ref>]]

DNA can be damaged by many sorts of [[mutagen]]s, which change the [[DNA sequencing|DNA sequence]]. Mutagens include [[oxidizing agent]]s, [[Alkylation|alkylating agents]] and also high-energy [[electromagnetic radiation]] such as [[ultraviolet]] light and [[X-ray]]s. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing [[thymine dimer]]s, which are cross-links between pyrimidine bases.<ref>{{cite journal | vauthors = Douki T, Reynaud-Angelin A, Cadet J, Sage E | title = Bipyrimidine photoproducts rather than oxidative lesions are the main type of DNA damage involved in the genotoxic effect of solar UVA radiation | journal = Biochemistry | volume = 42 | issue = 30 | pages = 9221–26 | date = August 2003 | pmid = 12885257 | doi = 10.1021/bi034593c }}</ref> On the other hand, oxidants such as [[Radical (chemistry)|free radicals]] or [[hydrogen peroxide]] produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks.<ref>{{cite journal | vauthors = Cadet J, Delatour T, Douki T, Gasparutto D, Pouget JP, Ravanat JL, Sauvaigo S | title = Hydroxyl radicals and DNA base damage | journal = Mutation Research | volume = 424 | issue = 1–2 | pages = 9–21 | date = March 1999 | pmid = 10064846 | doi = 10.1016/S0027-5107(99)00004-4 | bibcode = 1999MRFMM.424....9C }}</ref> A typical human cell contains about 150,000 bases that have suffered oxidative damage.<ref>{{cite journal | vauthors = Beckman KB, Ames BN | title = Oxidative decay of DNA | journal = The Journal of Biological Chemistry | volume = 272 | issue = 32 | pages = 19633–36 | date = August 1997 | pmid = 9289489 | doi = 10.1074/jbc.272.32.19633 | doi-access = free }}</ref> Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce [[point mutation]]s, [[Genetic insertion|insertions]], [[Deletion (genetics)|deletions]] from the DNA sequence, and [[chromosomal translocation]]s.<ref>{{cite journal | vauthors = Valerie K, Povirk LF | title = Regulation and mechanisms of mammalian double-strand break repair | journal = Oncogene | volume = 22 | issue = 37 | pages = 5792–812 | date = September 2003 | pmid = 12947387 | doi = 10.1038/sj.onc.1206679 | doi-access = free }}</ref> These mutations can cause [[cancer]]. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.<ref name=Weinberg>{{cite news | url = https://www.nytimes.com/2010/12/28/health/28cancer.html | title = Unearthing Prehistoric Tumors, and Debate | newspaper = [[The New York Times]] | date = 28 December 2010 | vauthors = Johnson G | quote = If we lived long enough, sooner or later we all would get cancer. | url-status=live | archive-url = https://web.archive.org/web/20170624233156/http://www.nytimes.com/2010/12/28/health/28cancer.html | archive-date = 24 June 2017 | df = dmy-all }}</ref><ref>{{cite book |vauthors= Alberts B, Johnson A, Lewis J |title= Molecular biology of the cell |publisher= Garland Science |location= New York |year= 2002 |edition= 4th |chapter= The Preventable Causes of Cancer |isbn= 0-8153-4072-9 |chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK26897/ |quote= A certain irreducible background incidence of cancer is to be expected regardless of circumstances: mutations can never be absolutely avoided, because they are an inescapable consequence of fundamental limitations on the accuracy of DNA replication, as discussed in Chapter 5. If a human could live long enough, it is inevitable that at least one of his or her cells would eventually accumulate a set of mutations sufficient for cancer to develop. |display-authors= etal |url-status=live |archive-url= https://web.archive.org/web/20160102193148/http://www.ncbi.nlm.nih.gov/books/NBK26897/ |archive-date= 2 January 2016 |df= dmy-all }}</ref> DNA damages that are [[DNA damage (naturally occurring)|naturally occurring]], due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.<ref>{{cite book | veditors = Kimura H, Suzuki A | title = New Research on DNA Damage | date = 2008 | publisher = Nova Science Publishers | location = New York | isbn = 978-1-60456-581-2 | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K | chapter = Cancer and aging as consequences of un-repaired DNA damage | chapter-url = https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | pages = 1–47 | url-status=live | archive-url = https://web.archive.org/web/20141025091740/https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | archive-date = 25 October 2014 | df = dmy-all }}</ref><ref>{{cite journal | vauthors = Hoeijmakers JH | title = DNA damage, aging, and cancer | journal = The New England Journal of Medicine | volume = 361 | issue = 15 | pages = 1475–85 | date = October 2009 | pmid = 19812404 | doi = 10.1056/NEJMra0804615 }}</ref><ref>{{cite journal | vauthors = Freitas AA, de Magalhães JP | title = A review and appraisal of the DNA damage theory of ageing | journal = Mutation Research | volume = 728 | issue = 1–2 | pages = 12–22 | year = 2011 | pmid = 21600302 | doi = 10.1016/j.mrrev.2011.05.001 | bibcode = 2011MRRMR.728...12F }}</ref>

Many mutagens fit into the space between two adjacent base pairs, this is called ''[[intercalation (biochemistry)|intercalation]]''. Most intercalators are [[aromaticity|aromatic]] and planar molecules; examples include [[ethidium bromide]], [[acridine]]s, [[Daunorubicin|daunomycin]], and [[doxorubicin]]. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations.<ref>{{cite journal | vauthors = Ferguson LR, Denny WA | title = The genetic toxicology of acridines | journal = Mutation Research | volume = 258 | issue = 2 | pages = 123–60 | date = September 1991 | pmid = 1881402 | doi = 10.1016/0165-1110(91)90006-H }}</ref> As a result, DNA intercalators may be [[carcinogen]]s, and in the case of thalidomide, a [[teratogen]].<ref>{{cite journal | vauthors = Stephens TD, Bunde CJ, Fillmore BJ | title = Mechanism of action in thalidomide teratogenesis | journal = Biochemical Pharmacology | volume = 59 | issue = 12 | pages = 1489–99 | date = June 2000 | pmid = 10799645 | doi = 10.1016/S0006-2952(99)00388-3 }}</ref> Others such as [[benzo(a)pyrene|benzo[''a'']pyrene diol epoxide]] and [[aflatoxin]] form DNA adducts that induce errors in replication.<ref>{{cite journal | vauthors = Jeffrey AM | title = DNA modification by chemical carcinogens | journal = Pharmacology & Therapeutics | volume = 28 | issue = 2 | pages = 237–72 | year = 1985 | pmid = 3936066 | doi = 10.1016/0163-7258(85)90013-0 }}</ref> Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in [[chemotherapy]] to inhibit rapidly growing [[cancer]] cells.<ref>{{cite journal | vauthors = Braña MF, Cacho M, Gradillas A, de Pascual-Teresa B, Ramos A | title = Intercalators as anticancer drugs | journal = Current Pharmaceutical Design | volume = 7 | issue = 17 | pages = 1745–80 | date = November 2001 | pmid = 11562309 | doi = 10.2174/1381612013397113 }}</ref>