BRCA1: Perbedaan antara revisi

BRCA1 dapat secara langsung berikatan dengan DNA, dengan afinitas yang lebih tinggi untuk struktur DNA yang bercabang (''branched structure''). Kemampuan untuk mengikat DNA ini berperan pada kemampuan BRCA1 dalam menghambat aktivitas nuklease kompleks MRN, juga aktivitas nuklease Mre11.<ref>{{Cite journal|last=Paull|first=Tanya T.|last2=Cortez|first2=David|last3=Bowers|first3=Blair|last4=Elledge|first4=Stephen J.|last5=Gellert|first5=Martin|date=2001-05-22|title=Direct DNA binding by Brca1|url=https://pnas.org/doi/full/10.1073/pnas.111125998|journal=Proceedings of the National Academy of Sciences|language=en|volume=98|issue=11|pages=6086–6091|doi=10.1073/pnas.111125998|issn=0027-8424|pmc=PMC33426|pmid=11353843}}</ref> Hal ini dapat menjelaskan peran BRCA1 untuk memfasilitasi perbaikan DNA dengan ketepatan yang lebih rendah melalui penggabungan ujung non-homolog (''non-homologous end joining'', NHEJ).<ref>{{Cite journal|last=Durant|first=Stephen T.|last2=Nickoloff|first2=Jac A|date=2005-09-22|title=Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1|url=https://www.tandfonline.com/doi/full/10.4161/cc.4.9.2027|journal=Cell Cycle|language=en|volume=4|issue=9|pages=1216–1222|doi=10.4161/cc.4.9.2027|issn=1538-4101}}</ref> BRCA1 juga berkolokalisasi dengan γ-H2AX (histon H2AX terfosforilasi pada serine-139) dalam perbaikan kerusakan untai ganda DNA, yang mengindikasikan bahwa BRCA1 juga berperan dalam merekrut faktor-faktor perbaikan DNA.<ref>{{Cite journal|last=Starita|first=L|date=2003-06|title=The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair|url=https://linkinghub.elsevier.com/retrieve/pii/S0955067403000425|journal=Current Opinion in Cell Biology|language=en|volume=15|issue=3|pages=345–350|doi=10.1016/S0955-0674(03)00042-5}}</ref>

 

Ekspresi ''BRCA1'' berkurang atau tidak terdeteksi pada sebagian besar kanker payudara duktal tingkat tinggi (''high grade ductal breast cancers'').<ref>{{Cite journal|last=Wilson|first=Cindy A.|last2=Ramos|first2=Lillian|last3=Villaseñor|first3=Maria R.|last4=Anders|first4=Karl H.|last5=Press|first5=Michael F.|last6=Clarke|first6=Kathy|last7=Karlan|first7=Beth|last8=Chen|first8=Jun-Jie|last9=Scully|first9=Ralph|date=1999-02|title=Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas|url=https://www.nature.com/articles/ng0299_236|journal=Nature Genetics|language=en|volume=21|issue=2|pages=236–240|doi=10.1038/6029|issn=1061-4036}}</ref> Telah lama diketahui bahwa hilangnya aktivitas BRCA1, baik karena mutasi ''germ-line'' maupun karena penurunan regulasi ekspresi gen, menyebabkan pembentukan tumor pada jaringan-jaringan tertentu. Secara khusus, penurunan ekspresi ''BRCA1'' berkontribusi pada perkembangan tumor payudara sporadis (tidak diwariskan, terjadi secara spontan) dan yang diwariskan.<ref>{{Cite journal|last=Mueller|first=Christopher R|last2=Roskelley|first2=Calvin D|date=2002-02|title=Regulation of BRCA1 expression and its relationship to sporadic breast cancer|url=http://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr557|journal=Breast Cancer Research|language=en|volume=5|issue=1|doi=10.1186/bcr557|issn=1465-542X|pmc=PMC154136|pmid=12559046}}</ref> Ekspresi ''BRCA1'' yang menurun bersifat tumorigenik, karena penurunan ekspresi ini memaikan peran penting dalam perbaikan kerusakan DNA, terutama pemutusan untai ganda, melalui jalur rekombinasi homolog yang berpotensi bebas dari kesalahan.<ref name=":4">{{Cite journal|last=Jacinto|first=F. V.|last2=Esteller|first2=M.|date=2007-07-01|title=Mutator pathways unleashed by epigenetic silencing in human cancer|url=https://academic.oup.com/mutage/article-lookup/doi/10.1093/mutage/gem009|journal=Mutagenesis|language=en|volume=22|issue=4|pages=247–253|doi=10.1093/mutage/gem009|issn=0267-8357}}</ref> Karena sel yang kekurangan protein BRCA1 cenderung memperbaiki kerusakan DNA dengan mekanisme alternatif yang lebih rentan terhadap kesalahan, penurunan atau penonaktifan protein ini menghasilkan mutasi dan penataan ulang kromosom (''chromosomal rearrangemen)'' yang dapat menyebabkan progresi kanker payudara.<ref name=":4" />

 

== Interaksi Protein ==

BRCA1 telah terbukti berinteraksi dengan protein-protein berikut:

* [[Abl gene|ABL1]]<ref name="pmid12024016">{{cite journal | vauthors = Foray N, Marot D, Randrianarison V, Venezia ND, Picard D, Perricaudet M, Favaudon V, Jeggo P | title = Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation | journal = Mol. Cell. Biol. | volume = 22 | issue = 12 | pages = 4020–32 | date = June 2002 | pmid = 12024016 | pmc = 133860 | doi = 10.1128/MCB.22.12.4020-4032.2002 }}</ref>

* [[AKT1]]<ref name="pmid10542266">{{cite journal | vauthors = Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H | title = Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells | journal = J. Biol. Chem. | volume = 274 | issue = 45 | pages = 32274–8 | date = November 1999 | pmid = 10542266 | doi = 10.1074/jbc.274.45.32274 | doi-access = free }}</ref><ref name="pmid19074868">{{cite journal | vauthors = Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN, Yang Q | title = Negative Regulation of AKT Activation by BRCA1 | journal = Cancer Res. | volume = 68 | issue = 24 | pages = 10040–4 | date = December 2008 | pmid = 19074868 | pmc = 2605656 | doi = 10.1158/0008-5472.CAN-08-3009 }}</ref>

* [[RAD51]]<ref name="pmid9774970">{{cite journal | vauthors = Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R | title = Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells | journal = Mol. Cell | volume = 2 | issue = 3 | pages = 317–28 | date = September 1998 | pmid = 9774970 | doi = 10.1016/S1097-2765(00)80276-2 | doi-access = free }}</ref><ref name="pmid9008167">{{cite journal | vauthors = Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM | title = Association of BRCA1 with Rad51 in mitotic and meiotic cells | journal = Cell | volume = 88 | issue = 2 | pages = 265–75 | date = January 1997 | pmid = 9008167 | doi = 10.1016/S0092-8674(00)81847-4 | doi-access = free }}</ref>

* [[RBBP4]]

 

== Referensi ==

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[[Kategori: Gen penekan tumor]]