BRCA1

BRCA1
Struktur yang tersedia PDB Pencarian Ortolog: PDBe RCSB Daftar kode id PDB 1JM7, 1JNX, 1N5O, 1OQA, 1T15, 1T29, 1T2U, 1T2V, 1Y98, 2ING, 3COJ, 3K0H, 3K0K, 3K15, 3PXA, 3PXB, 3PXC, 3PXD, 3PXE, 4IFI, 4IGK, 4JLU, 4OFB, 4U4A, 4Y18, 4Y2G
Pengidentifikasi
Alias	BRCA1, breast cancer 1, early onset, BRCAI, BRCC1, BROVCA1, IRIS, PNCA4, PPP1R53, PSCP, RNF53, FANCS, breast cancer 1, DNA repair associated, BRCA1 DNA repair associated, Genes
ID eksternal	OMIM: 113705 MGI: 104537 HomoloGene: 5276 GeneCards: BRCA1
Lokasi gen (Tikus) Kr. Kromosom 11 (tikus)[1] Pita 11 65.18 cM|11 D Awal 101,379,590 bp[1] Akhir 101,442,781 bp[1]
Pola ekspresi RNA Referensi data ekspresi selengkapnya
Ontologi gen Fungsi molekuler • tubulin binding • metal ion binding • enzyme binding • zinc ion binding • damaged DNA binding • GO:0001948, GO:0016582 Ikatan protein plasma • GO:0001105 transcription coactivator activity • androgen receptor binding • RNA binding • ubiquitin protein ligase binding • GO:0050372 ubiquitin-protein transferase activity • DNA binding • transferase activity • RNA polymerase binding • pengikatan protein identik Komponen seluler • BRCA1-BARD1 complex • condensed nuclear chromosome • BRCA1-A complex • ubiquitin ligase complex • Membran sel • nucleoplasm • condensed chromosome • sitoplasma • kromosom • Inti sel • lateral element • GO:0009327 protein-containing complex • ribonucleoprotein complex Proses biologis • response to ionizing radiation • centrosome cycle • chromosome segregation • protein K6-linked ubiquitination • intrinsic apoptotic signaling pathway in response to DNA damage • Siklus sel • double-strand break repair via nonhomologous end joining • GO:0097285 Apoptosis • regulation of apoptotic process • regulation of gene expression by genetic imprinting • GO:0009373 regulation of transcription, DNA-templated • negative regulation of fatty acid biosynthetic process • transcription, DNA-templated • regulation of transcription by RNA polymerase III • fatty acid biosynthetic process • regulation of DNA methylation • negative regulation of intracellular estrogen receptor signaling pathway • protein autoubiquitination • positive regulation of histone H3-K9 methylation • DNA recombination • positive regulation of angiogenesis • response to estrogen • cellular response to indole-3-methanol • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • GO:0045996 negative regulation of transcription, DNA-templated • positive regulation of protein ubiquitination • androgen receptor signaling pathway • negative regulation of centriole replication • postreplication repair • metabolisme lipid • cellular response to tumor necrosis factor • GO:1900404 positive regulation of DNA repair • Metabolisme asam lemak • GO:1901313 positive regulation of gene expression • negative regulation of histone H3-K4 methylation • regulation of cell population proliferation • negative regulation of reactive oxygen species metabolic process • positive regulation of vascular endothelial growth factor production • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • positive regulation of histone H4-K20 methylation • DNA double-strand break processing • double-strand break repair via homologous recombination • negative regulation of histone acetylation • protein ubiquitination • positive regulation of histone H3-K4 methylation • GO:0100026 Reparasi DNA • double-strand break repair • positive regulation of histone acetylation • dosage compensation by inactivation of X chromosome • negative regulation of histone H3-K9 methylation • positive regulation of histone H3-K9 acetylation • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • chordate embryonic development • positive regulation of histone H4-K16 acetylation • cellular response to DNA damage stimulus • protein deubiquitination • Replikasi DNA • mitotic G2/M transition checkpoint • GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II • negative regulation of G0 to G1 transition • transcription by RNA polymerase II • mitotic G2 DNA damage checkpoint signaling • regulation of signal transduction by p53 class mediator Sumber:Amigo / QuickGO
Ortolog
Spesies	Manusia	Tikus
Entrez	672	12189
Ensembl	ENSG00000012048	ENSMUSG00000017146
UniProt	P38398	P48754
RefSeq (mRNA)	NM_007294 NM_007295 NM_007296 NM_007297 NM_007298 NM_007299 NM_007300 NM_007301 NM_007302 NM_007303 NM_007305 NM_007306	NM_009764
RefSeq (protein)	NP_009225 NP_009228 NP_009229 NP_009230 NP_009231	NP_033894
Lokasi (UCSC)	n/a	Chr 11: 101.38 – 101.44 Mb
Pencarian PubMed	[2]	[3]
Wikidata
Lihat/Sunting Manusia Lihat/Sunting Tikus

Breast cancer type 1 susceptibility protein adalah protein yang pada manusia dikodekan oleh gen BRCA1. BRCA1 adalah gen penekan tumor (tumor supressor) pada manusia dan bertanggung jawab untuk memperbaiki kerusakan DNA.^[4][5] Ortolog dari gen ini umum ditemukan pada spesies vertebrata lain selain manusia, sedangkan genom invertebrata mengkodekan gen terkait yang berkerabat jauh.^[6]

BRCA1 dan BRCA2 adalah protein yang tidak saling berhubungan,^[7] tetapi keduanya biasanya diekspresikan dalam sel payudara dan jaringan lain, di mana mereka membantu memperbaiki DNA yang rusak, atau menghancurkan sel jika DNA tidak dapat diperbaiki.^[8][4] Keduanya terlibat dalam perbaikan kerusakan kromosom dengan peran penting dalam perbaikan kerusakan untai ganda DNA.^[9][4]

Jika BRCA1 atau BRCA2 itu sendiri rusak akibat mutasi BRCA, maka DNA yang rusak tidak dapat diperbaiki dengan baik, dan hal ini meningkatkan risiko terjadinya kanker payudara.^[8][9] Alel dominan memiliki fungsi penekan tumor yang normal, sedangkan mutasi penetrasi tinggi pada gen-gen ini menyebabkan hilangnya fungsi penekan tumor yang berkorelasi dengan peningkatan risiko kanker payudara.^[10]

BRCA1 berasosiasi dengan protein penekan tumor lainnya, protein sensor kerusakan DNA, dan transduser sinyal untuk membentuk kompleks protein multi-subunit besar yang dikenal sebagai kompleks pengawasan genom yang terasosiasi dengan BRCA1 (BRCA1-associated genome surveillance complex, BASC).^[11] Protein BRCA1 berasosiasi dengan RNA polimerase II, dan melalui domain C-terminal, juga berinteraksi dengan kompleks histone deacetylase.^[9] Dengan demikian, protein ini berperan dalam transkripsi, dan perbaikan DNA dari kerusakan DNA untai ganda ubiquitinasi, regulasi transkripsi, serta fungsi lainnya.^[12]

Bukti pertama keberadaan gen yang mengkode enzim perbaikan DNA yang terlibat dalam risiko terjadinya kanker payudara dikemukakan oleh laboratorium Mary-Claire King di UC Berkeley pada tahun 1990.^[13] Empat tahun kemudian, setelah terjadi perlombaan internasional untuk menemukannya,^[14] gen tersebut dikloning pada tahun 1994 oleh para ilmuwan di University of Utah, National Institute of Environmental Health Sciences (NIEHS), dan Myriad Genetics.^[15]

Gen BRCA1 manusia terletak pada lengan panjang (q) kromosom 17 di wilayah 2 pita 1, dari pasangan basa 41.196.312 hingga pasangan basa 41.277.500 (Build GRCh37 / HG19).^[16] Ortolog BRCA1 telah diidentifikasi pada sebagian besar vertebrata yang memiliki data genom lengkap.^[6]

BRCA1 adalah bagian dari kompleks protein yang berfungsi memperbaiki kerusakan untai ganda pada DNA. Ketika DNA mengalami kerusakan, untaian pada DNA tersebut akan terputus. Terkadang hanya satu untai yang putus, terkadang kedua untai putus secara bersamaan. Agen pengikat silang DNA (DNA cross-linking agent) adalah salah satu penyebab utama dari kerusakan kromosom dan DNA. Pemutusan untai ganda (double strand breaks) terjadi sebagai intermediet setelah ikatan silang ini dihilangkan. Mutasi bialelik pada BRCA1 telah diidentifikasi bertanggung jawab atas Anemia Fanconi, Complementation Group S (FA-S), penyakit genetik yang terkait dengan hipersensitivitas terhadap agen pengikat silang DNA.^[17]

BRCA1 adalah bagian dari kompleks protein yang memperbaiki DNA ketika kedua untaiannya rusak. Ketika hal ini terjadi, sulit bagi mekanisme perbaikan untuk "mengetahui" cara mengganti urutan DNA yang benar. Ditambah lagi, terdapat berbagai mekanisme perbaikan DNA yang dapat dicoba. Mekanisme perbaikan untai ganda yang melibatkan BRCA1 adalah perbaikan yang diarahkan oleh homologi (homology-directed repair), di mana protein perbaikan menyalin urutan yang identik dari kromatid saudara (sister chromatid) yang masih utuh.^[18]

Di dalam nukleus dari berbagai jenis sel normal, protein BRCA1 berinteraksi dengan RAD51 selama perbaikan kerusakan untai ganda DNA.^[19] Selain karena radiasi alami atau paparan yang lain, kerusakan ini dapat juga disebabkan ketika kromosom bertukar materi genetik, seperti pada proses rekombinasi homolog (contohnya, crossing over dalam pembelah meiosis). Protein BRCA2, yang memiliki fungsi yang mirip dengan BRCA1, juga berinteraksi dengan protein RAD51. Karena berperan dalam proses perbaikan kerusakan DNA, ketiga protein ini berperan penting dalam menjaga stabilitas genom manusia.^[20]

BRCA1 juga terlibat dalam jenis perbaikan DNA lainnya, yang disebut perbaikan mismatch. BRCA1 berinteraksi dengan protein perbaikan mismatch DNA MSH2.^[21] Eksperesi MSH2, MSH6, PARP, dan beberapa protein lain yang terlibat dalam perbaikan untai tunggal diketahui meningkat pada tumor payudara yang memiliki defisiensi BRCA1.^[22]

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.^[23] 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).^[24] 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.^[25]

Ekspresi BRCA1 berkurang atau tidak terdeteksi pada sebagian besar kanker payudara duktal tingkat tinggi (high grade ductal breast cancers).^[26] 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.^[27] 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.^[28] 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.^[28]

BRCA1 telah terbukti berinteraksi dengan protein-protein berikut:

• ABL1^[29]
• AKT1^[30][31]
• AR^[32]
• ATR^{[33][34][35][36]}
• ATM^{[33][34][36][37]}
• ATF1
• BACH1^[38]
• BARD1^[38]
• BRCA2^[39]
• BRCC3
• BRE
• BRIP1^[40][41][42]
• C-jun
• CHEK2^[43][44]
• CLSPN^[45]
• COBRA1^[46]
• CREBBP^{[47][48][49][50][51]}
• CSNK2B^[52]
• CSTF2^[53][54]
• CDK2^[55][56][57]
• DHX9^[58][59]
• ELK4^[60]
• EP300^[48][50]
• ESR1^{[50][61][62][63]}
• FANCA^[64]
• FANCD2^[65]
• FHL2^[66][67]
• H2AFX^[68]
• JUNB^[69]
• JunD^[69]
• LMO4^[70][71]
• MAP3K3^[72]
• MED1^[73]
• MED17^[74][73][75]
• MED21^[76]
• MED24^[73]
• MRE11A^{[77][74][78][79]}
• MSH2^[77]
• MSH3^[80]
• MSH6^[77]
• Myc^[81][82][83]
• NBN^[77][74][78]
• NMI^[81]
• NPM1
• NCOA2^[84]
• NUFIP1^[85]
• P53^{[49][86][87][88]}
• PALB2^[89]
• POLR2A^{[74][76][90][91]}
• PPP1CA^[92]
• Rad50^[77][74][78]
• RAD51^[93][94]
• RBBP4

1. ^ ^{a b c} GRCm38: Ensembl release 89: ENSMUSG00000017146 - Ensembl, May 2017
2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine. 
3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine. 
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17. ^ Sawyer, Sarah L.; Tian, Lei; Kähkönen, Marketta; Schwartzentruber, Jeremy; Kircher, Martin; University of Washington Centre for Mendelian Genomics; FORGE Canada Consortium; Majewski, Jacek; Dyment, David A. (2015-02-01). "Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype". Cancer Discovery (dalam bahasa Inggris). 5 (2): 135–142. doi:10.1158/2159-8290.CD-14-1156. ISSN 2159-8274. PMC 4320660 . PMID 25472942. Pemeliharaan CS1: Format PMC (link)
18. ^ Domchek, Susan M.; Tang, Jiangbo; Stopfer, Jill; Lilli, Dana R.; Hamel, Nancy; Tischkowitz, Marc; Monteiro, Alvaro N.A.; Messick, Troy E.; Powers, Jacquelyn (2013-04-01). "Biallelic Deleterious BRCA1 Mutations in a Woman with Early-Onset Ovarian Cancer". Cancer Discovery (dalam bahasa Inggris). 3 (4): 399–405. doi:10.1158/2159-8290.CD-12-0421. ISSN 2159-8274. PMC 3625496 . PMID 23269703. Pemeliharaan CS1: Format PMC (link)
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20. ^ Roy, Rohini; Chun, Jarin; Powell, Simon N. (2012-01). "BRCA1 and BRCA2: different roles in a common pathway of genome protection". Nature Reviews Cancer (dalam bahasa Inggris). 12 (1): 68–78. doi:10.1038/nrc3181. ISSN 1474-175X. PMC 4972490 . PMID 22193408.  Periksa nilai tanggal di: |date= (bantuan)Pemeliharaan CS1: Format PMC (link)
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22. ^ Warmoes, Marc; Jaspers, Janneke E.; Pham, Thang V.; Piersma, Sander R.; Oudgenoeg, Gideon; Massink, Maarten P.G.; Waisfisz, Quinten; Rottenberg, Sven; Boven, Epie (2012-07). "Proteomics of Mouse BRCA1-deficient Mammary Tumors Identifies DNA Repair Proteins with Potential Diagnostic and Prognostic Value in Human Breast Cancer". Molecular & Cellular Proteomics (dalam bahasa Inggris). 11 (7): M111.013334–1–M111.013334–19. doi:10.1074/mcp.M111.013334. PMC 3394939 . PMID 22366898.  Periksa nilai tanggal di: |date= (bantuan)Pemeliharaan CS1: Format PMC (link)
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Wikimedia Commons memiliki media mengenai BRCA1.

• MeSH BRCA1 Protein
• MeSH Genes, BRCA1
• PDBe-KB memberikan gambaran umum tentang semua informasi struktur yang tersedia dalam PDB untuk protein BRCA1 manusia.