Editing Histone (section)

==== DNA damage repair ====

Marking sites of DNA damage is an important function for histone modifications. Without a repair marker, DNA would get destroyed by damage accumulated from sources such as the [[ultraviolet radiation]] of the sun.
; ''Phosphorylation of H2AX at serine 139 (γH2AX)'': Phosphorylated [[H2AX]] (also known as gamma H2AX) is a marker for [[DNA double strand breaks]],<ref name="pmid9488723">{{cite journal | vauthors = Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM | title = DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 10 | pages = 5858–68 | date = March 1998 | pmid = 9488723 | doi = 10.1074/jbc.273.10.5858 | doi-access = free }}</ref> and forms part of the [[DNA repair#Global response to DNA damage|response to DNA damage]].<ref name="pmid10959836"/><ref>{{cite journal | vauthors = Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A | title = Genomic instability in mice lacking histone H2AX | journal = Science | volume = 296 | issue = 5569 | pages = 922–7 | date = May 2002 | pmid = 11934988 | pmc = 4721576 | doi = 10.1126/science.1069398 | bibcode = 2002Sci...296..922C }}</ref> H2AX is phosphorylated early after detection of DNA double strand break, and forms a domain extending many kilobases either side of the damage.<ref name="pmid9488723"/><ref>{{cite journal | vauthors = Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M | title = Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break | journal = Current Biology | volume = 14 | issue = 19 | pages = 1703–11 | date = October 2004 | pmid = 15458641 | pmc = 4493763 | doi = 10.1016/j.cub.2004.09.047 | bibcode = 2004CBio...14.1703S }}</ref><ref>{{cite journal | vauthors = Rogakou EP, Boon C, Redon C, Bonner WM | title = Megabase chromatin domains involved in DNA double-strand breaks in vivo | journal = The Journal of Cell Biology | volume = 146 | issue = 5 | pages = 905–16 | date = September 1999 | pmid = 10477747 | pmc = 2169482 | doi = 10.1083/jcb.146.5.905 }}</ref> Gamma H2AX acts as a binding site for the protein MDC1, which in turn recruits key DNA repair proteins<ref>{{cite journal |vauthors=Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ |date=February 2003 |title=MDC1 is a mediator of the mammalian DNA damage checkpoint |url=https://www.nature.com/articles/nature01446 |journal=Nature |volume=421 |issue=6926 |pages=961–6 |bibcode=2003Natur.421..961S |doi=10.1038/nature01446 |pmid=12607005 |s2cid=4410773}}</ref> (this complex topic is well reviewed in<ref>{{cite journal |vauthors=Bekker-Jensen S, Mailand N |date=December 2010 |title=Assembly and function of DNA double-strand break repair foci in mammalian cells |url=https://www.sciencedirect.com/science/article/abs/pii/S1568786410003150 |journal=DNA Repair |volume=9 |issue=12 |pages=1219–28 |doi=10.1016/j.dnarep.2010.09.010 |pmid=21035408}}</ref>) and as such, gamma H2AX forms a vital part of the machinery that ensures genome stability.
;''Acetylation of H3 lysine 56 (H3K56Ac)'': H3K56Acx is required for genome stability.<ref>{{cite journal | vauthors = Ozdemir A, Spicuglia S, Lasonder E, Vermeulen M, Campsteijn C, Stunnenberg HG, Logie C | title = Characterization of lysine 56 of histone H3 as an acetylation site in Saccharomyces cerevisiae | journal = The Journal of Biological Chemistry | volume = 280 | issue = 28 | pages = 25949–52 | date = July 2005 | pmid = 15888442 | doi = 10.1074/jbc.C500181200 | doi-access = free | hdl = 2066/32314 | hdl-access = free }}</ref><ref>{{cite journal |vauthors=Masumoto H, Hawke D, Kobayashi R, Verreault A |date=July 2005 |title=A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response |url=https://www.nature.com/articles/nature03714 |journal=Nature |volume=436 |issue=7048 |pages=294–8 |bibcode=2005Natur.436..294M |doi=10.1038/nature03714 |pmid=16015338 |s2cid=4414433}}</ref> H3K56 is acetylated by the p300/Rtt109 complex,<ref>{{cite journal | vauthors = Driscoll R, Hudson A, Jackson SP | title = Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56 | journal = Science | volume = 315 | issue = 5812 | pages = 649–52 | date = February 2007 | pmid = 17272722 | pmc = 3334813 | doi = 10.1126/science.1135862 | bibcode = 2007Sci...315..649D }}</ref><ref>{{cite journal |vauthors=Han J, Zhou H, Horazdovsky B, Zhang K, Xu RM, Zhang Z |date=February 2007 |title=Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication |url=https://www.science.org/doi/10.1126/science.1133234 |journal=Science |volume=315 |issue=5812 |pages=653–5 |bibcode=2007Sci...315..653H |doi=10.1126/science.1133234 |pmid=17272723 |s2cid=19056605}}</ref><ref>{{cite journal | vauthors = Das C, Lucia MS, Hansen KC, Tyler JK | title = CBP/p300-mediated acetylation of histone H3 on lysine 56 | journal = Nature | volume = 459 | issue = 7243 | pages = 113–7 | date = May 2009 | pmid = 19270680 | pmc = 2756583 | doi = 10.1038/nature07861 | bibcode = 2009Natur.459..113D }}</ref> but is rapidly deacetylated around sites of DNA damage. H3K56 acetylation is also required to stabilise stalled replication forks, preventing dangerous replication fork collapses.<ref>{{cite journal | vauthors = Han J, Zhou H, Li Z, Xu RM, Zhang Z | title = Acetylation of lysine 56 of histone H3 catalyzed by RTT109 and regulated by ASF1 is required for replisome integrity | journal = The Journal of Biological Chemistry | volume = 282 | issue = 39 | pages = 28587–96 | date = September 2007 | pmid = 17690098 | doi = 10.1074/jbc.M702496200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wurtele H, Kaiser GS, Bacal J, St-Hilaire E, Lee EH, Tsao S, Dorn J, Maddox P, Lisby M, Pasero P, Verreault A | title = Histone H3 lysine 56 acetylation and the response to DNA replication fork damage | journal = Molecular and Cellular Biology | volume = 32 | issue = 1 | pages = 154–72 | date = January 2012 | pmid = 22025679 | pmc = 3255698 | doi = 10.1128/MCB.05415-11 }}</ref> Although in general mammals make far greater use of histone modifications than microorganisms, a major role of H3K56Ac in DNA replication exists only in fungi, and this has become a target for antibiotic development.<ref>{{cite journal | vauthors = Wurtele H, Tsao S, Lépine G, Mullick A, Tremblay J, Drogaris P, Lee EH, Thibault P, Verreault A, Raymond M | title = Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy | journal = Nature Medicine | volume = 16 | issue = 7 | pages = 774–80 | date = July 2010 | pmid = 20601951 | pmc = 4108442 | doi = 10.1038/nm.2175 }}</ref>
; ''Trimethylation of H3 lysine 36 (H3K36me3)''
:H3K36me3 has the ability to recruit the MSH2-MSH6 (hMutSα) complex of the [[DNA mismatch repair]] pathway.<ref>{{cite journal | vauthors = Li F, Mao G, Tong D, Huang J, Gu L, Yang W, Li GM | title = The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα | journal = Cell | volume = 153 | issue = 3 | pages = 590–600 | date = April 2013 | pmid = 23622243 | pmc = 3641580 | doi = 10.1016/j.cell.2013.03.025 }}</ref> Consistently, regions of the human genome with high levels of H3K36me3 accumulate less somatic mutations due to [[DNA mismatch repair|mismatch repair]] activity.<ref>{{cite journal | vauthors = Supek F, Lehner B | title = Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes | journal = Cell | volume = 170 | issue = 3 | pages = 534–547.e23 | date = July 2017 | pmid = 28753428 | doi = 10.1016/j.cell.2017.07.003 | doi-access = free | hdl = 10230/35343 | hdl-access = free }}</ref>