Editing BRCA2 (section)

== Function ==
[[File:Homologous recombinational repair of DNA double-strand damage.jpg|thumb|300px|'''Recombinational repair of DNA double-strand damage - some key steps.'''  [[Ataxia telangiectasia mutated|ATM]] (ATM) is a [[protein kinase]] that is recruited and activated by [[DNA repair#Double-strand breaks|DNA double-strand breaks]].  DNA double-strand damages also activate the [[FANC proteins|Fanconi anemia core complex]] (FANCA/B/C/E/F/G/L/M).<ref name="pmid20484397">{{cite journal |vauthors=D'Andrea AD |title=Susceptibility pathways in Fanconi's anemia and breast cancer |journal=N. Engl. J. Med. |volume=362 |issue=20 |pages=1909–19 |year=2010 |pmid=20484397 |pmc=3069698 |doi=10.1056/NEJMra0809889 }}</ref>  The FA core complex [[ubiquitin|monoubiquitinates]] the downstream targets FANCD2 and FANCI.<ref name="pmid19633289">{{cite journal |vauthors=Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME |title=The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways |journal=J. Biol. Chem. |volume=284 |issue=38 |pages=25560–8 |year=2009 |pmid=19633289 |pmc=2757957 |doi=10.1074/jbc.M109.007690 |doi-access=free }}</ref>   ATM activates (phosphorylates) [[CHEK2]] and [[FANCD2]]<ref name=Castillo>{{cite journal |vauthors=Castillo P, Bogliolo M, Surralles J |title=Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage |journal=DNA Repair (Amst.) |volume=10 |issue=5 |pages=518–25 |year=2011 |pmid=21466974 |doi=10.1016/j.dnarep.2011.02.007 }}</ref>  CHEK2 phosphorylates BRCA1.<ref name="pmid21088254">{{cite journal |vauthors=Stolz A, Ertych N, Bastians H |title=Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability |journal=Clin. Cancer Res. |volume=17 |issue=3 |pages=401–5 |year=2011 |pmid=21088254 |doi=10.1158/1078-0432.CCR-10-1215 |doi-access=free }}</ref>   Ubiquinated FANCD2 complexes with [[BRCA1]] and [[RAD51]].<ref name="pmid12239151">{{cite journal |vauthors=Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD |title=S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51 |journal=Blood |volume=100 |issue=7 |pages=2414–20 |year=2002 |pmid=12239151 |doi=10.1182/blood-2002-01-0278 |doi-access=free }}</ref>  The [[PALB2]] protein acts as a hub,<ref name="pmid24998779">{{cite journal |vauthors=Park JY, Zhang F, Andreassen PR |title=PALB2: the hub of a network of tumor suppressors involved in DNA damage responses |journal=Biochim. Biophys. Acta |volume=1846 |issue=1 |pages=263–75 |year=2014 |pmid=24998779 |pmc=4183126 |doi=10.1016/j.bbcan.2014.06.003 }}</ref> bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex [[RAD51L1|RAD51B]]-[[RAD51C]]-[[RAD51L3|RAD51D]]-[[XRCC2]] (BCDX2).  The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.<ref name=Chun>{{cite journal |vauthors=Chun J, Buechelmaier ES, Powell SN |title=Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway |journal=Mol. Cell. Biol. |volume=33 |issue=2 |pages=387–95 |year=2013 |pmid=23149936 |pmc=3554112 |doi=10.1128/MCB.00465-12 }}</ref>  [[RAD51]] plays a major role in [[homologous recombination]]al repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules.  RAD51 is involved in the search for homology and strand pairing stages of the process.]]

Although the structures of the ''[[BRCA1]]'' and ''BRCA2'' genes are very different, at least some functions are interrelated. The [[protein]]s made by both [[gene]]s are essential for repairing damaged DNA (see Figure of recombinational repair steps). BRCA2 binds the single strand DNA and directly interacts with the recombinase [[RAD51]] to stimulate<ref>{{cite journal | vauthors = Jensen RB, Carreira A, Kowalczykowski SC | title = Purified human BRCA2 stimulates RAD51-mediated recombination | journal = Nature | volume = 467 | issue = 7316 | pages = 678–83 | date = October 2010 | pmid = 20729832 | pmc = 2952063 | doi = 10.1038/nature09399 | bibcode = 2010Natur.467..678J }}</ref> and maintain <ref>{{cite journal | vauthors = Wang CX, Jimenez-Sainz J, Jensen RB, Mazin AV | title = The Post-Synaptic Function of Brca2 | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 4554 | date = March 2019 | pmid = 30872704 | doi = 10.1038/s41598-019-41054-y | pmc=6418147| bibcode = 2019NatSR...9.4554W }}</ref> strand invasion, a vital step of [[homologous recombination]]. The localization of RAD51 to the DNA double-strand break requires the formation of the BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2)<ref name="pmid16793542">{{cite journal | vauthors = Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM | title = Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2 | journal = Molecular Cell | volume = 22 | issue = 6 | pages = 719–29 | date = June 2006 | pmid = 16793542 | doi = 10.1016/j.molcel.2006.05.022 | doi-access = free }}</ref> can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.<ref name="Buisson_2010">{{cite journal | vauthors = Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H, Stasiak AZ, Stasiak A, Xia B, Masson JY | title = Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination | journal = Nature Structural & Molecular Biology | volume = 17 | issue = 10 | pages = 1247–54 | date = October 2010 | pmid = 20871615 | pmc = 4094107 | doi = 10.1038/nsmb.1915 }}</ref> These breaks can be caused by natural and medical radiation or other environmental exposures, but also occur when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs ([[meiosis]]). Double strand breaks are also generated during repair of DNA cross links. By repairing DNA, these proteins play a role in maintaining the stability of the [[human genome]] and prevent dangerous gene rearrangements that can lead to hematologic and other cancers.

BRCA2 has been shown to possess a crucial role in protection from the [[Mre11-Rad50-Xrs2|MRE11]]-dependent nucleolytic degradation of the [[reversed forks]] that are forming during [[DNA replication]] fork stalling (caused by obstacles such as mutations, intercalating agents etc.).<ref>{{cite journal | vauthors = Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K, Mutreja K, Ursich S, Ray Chaudhuri A, Nussenzweig A, Janscak P, Lopes M | title = Replication fork reversal triggers fork degradation in BRCA2-defective cells | language = En | journal = Nature Communications | volume = 8 | issue = 1 | pages = 859 | date = October 2017 | pmid = 29038466 | pmc = 5643541 | doi = 10.1038/s41467-017-01164-5 | bibcode = 2017NatCo...8..859M }}</ref>

Like BRCA1, BRCA2 probably regulates the activity of other genes and plays a critical role in embryo development.