RNR3
Ribosomna RNK 3, znana i kao RNR3, je ljudski gen.[2] To je manja izoforma velike podjedinice ribonukleotid-difosfat reduktaze; RNR kompleks katalizira korak ograničavanja brzine u sintezi dNTP, reguliran putem replikacije DNK i popravke oštećenja DNK putem lokalizacije malih podjedinica: RNR3 ima paralog, RNR1, koji je nastao iz umnožavanjs cijelog genoma.[3]
| RNR3 | |||||||
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| Identifikatori | |||||||
| Aliasi | RNR3 | ||||||
| Vanjski ID-jevi | OMIM: 180452 GeneCards: RNR3 | ||||||
| Ortolozi | |||||||
| Vrste | Čovjek | Miš | |||||
| Entrez |
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| UniProt |
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| RefSeq (mRNK) |
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| RefSeq (bjelančevina) |
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| Lokacija (UCSC) | n/a | n/a | |||||
| PubMed pretraga | [1] | n/a | |||||
| Wikipodaci | |||||||
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Ribonukleotid-reduktaza (RNR) je tetramerni proteinski kompleks koji katalizira konverziju nukleotida u dezoksinukleotide, korak koji ograničava brzinu u biosintezi de novo dezoksiribonukleotida i ima bitnu ulogu u replikaciji i popravku DNK . Uravnotežena opskrba dezoksiribonukleozid trifosfatima (dNTP) potrebna je za precizno dupliranje genoma. I ukupna koncentracija i ravnoteža između pojedinih dNTP (dATP, dTTP, dGTP i dCTP) strogo su regulirani ribonukleotid-reduktazom.[4][5] Aktivnost ribonukleotid-reduktaze je periodična, tokom ćelijskog ciklusa, raste od početnog niskog nivoa do maksimuma u ranoj S-fazi, a zatim opada na njenom kraju.[6][7]
Ribonukleotid-reduktaza sastoji se od dvije velike i dvije male podjedinice. U Saccharomyces cerevisiae, glavna izoforma velike podjedinice kodirana je RNR1, a druga izoforma RNR3; dvije male podjedinice kodirane su RNR2 i RNR4.[8] Homodimer Rnr1p: Rnr1p sadrži regulatorna i katalitska mjesta, a u heterodimeru Rnr2p: Rnr4p smješten je esencijalni kofaktor diferno-tirozil radikala . Ključna uloga Rnr4p je pravilno savijanje i stabilizirati Rnr2p koji pohranjuje radikale, formirajući stabilan kompleks Rnr2p/Rnr4p u omjeru 1: 1. Doprinos RNR3 redukciji ribonukleotida nije jasan. RNR3 se ne eksprimira tokom normalnog rasta, ali kao i ostale tri podjedinice snažno je induciran oštećenjem DNA, iako nikada ne doseže više od jedne desetine nivoa Rnr1p. Tokom većeg dijela ćelijskog ciklusa, Rnr1p i Rnr3p su lokalizirani u citoplazmi, dok su Rnr2p i Rnr4p prisutni u dru. Kao odgovor na S fazu ili oštećenje DNK, potkompleks Rnr2p: Rnr4p prolazi kroz redistribuciju jedra do citoplazme ovisne o kontrolnoj tački i veže homodimer Rnr1p, formirajući aktivni kompleks RNR. Dif1p kontrolira subćelijsku lokalizaciju potkompleksa Rnr2p: Rnr4p vezujući se izravno za njega i posredujući u njegovom jedarnom unosu. Wtm1p djeluje kao jedarno sidro za održavanje jedarne lokalizacije Rnr2p: Rnr4p izvan S-faze ili u odsustvu oštećenja DNK.[9][10][11]
Inhibicija aktivnosti ribonukleotid-reduktaze tretmanom hidroksiureje rezultira zaustavljanjem ćelijskog ciklusa S-faze i velikim pupoljcima, jednostrukim ćelijama. I RNR1 i RNR2 su bitni za održivost, dok RNR3 nije.[12][13][14][15]
Aleli RNR1 i RNR2 osjetljivi na temperaturu zaustavljaju se s pupoljkom, cdc terminalnim fenotipom na temperaturi koja nije permisivna. Prekomjerna ekspresija RNR3 potiskuje smrtonosnost nultih mutacija rnr1. Deletirane ćelije za RNR3 preosjetljive su na rapamicin plus MMS. Delecija RNR4 je u nekim sojevima smrtonosna, ali u drugima nije, a ta se smrtnost može suzbiti prekomjernom ekspresijom RNR1 i RNR3 ili RNR2. Neki nulti mutanti rnr4 pokazuju spor rast i osjetljivost na mutagene, uključujući UV svjetlost i psoralene, kao i povećanu osjetljivost na oksidativni stres.[16][17][18] Nulte mutirane ćelije rnr4 povećane su i također pokazuju veću učestalost pupanja, što ukazuje na kašnjenje mitoze/citokineze.
RNR je identificiran kod E. coli, biljaka i sisara. Budući da je aktivnost RNR presudna za brzo dijeljenje ćelija, njena prekomjerna ekspresija može dovesti do neoplazijske transformacije, što RNR čini metom za terapiju karcinoma. U ćelijama sisara, mala podjedinica RNR mjesto je djelovanja nekoliko antitumorskih sredstava, uključujući hidroksiureu i 4-metil-5-amino-1-formilizohinolin tiosemikarbazon (MAIQ).[19][20][21][22][23][24][25][26][27][28] [29][30][31][32]
Reference
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- ^ "Entrez Gene: RNR3 RNA, ribosomal 3".
- ^ https://www.yeastgenome.org/locus/RNR3
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- ^ Yao R, et al. (2003) Subcellular localization of yeast ribonucleotide reductase regulated by the DNA replication and damage checkpoint pathways. Proc Natl Acad Sci U S A 100(11):6628-33 PMID 12732713
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- ^ An X, et al. (2006) Cotransport of the heterodimeric small subunit of the Saccharomyces cerevisiae ribonucleotide reductase between the nucleus and the cytoplasm. Genetics 173(1):63-73 PMID 16489218
- ^ Kumar D, et al. (2010) Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res 38(12):3975-83 PMID 20215435
- ^ Wu X and Huang M (2008) Dif1 controls subcellular localization of ribonucleotide reductase by mediating nuclear import of the R2 subunit. Mol Cell Biol 28(23):7156-67 PMID 18838542
- ^ Zhang Z, et al. (2006) Nuclear localization of the Saccharomyces cerevisiae ribonucleotide reductase small subunit requires a karyopherin and a WD40 repeat protein. Proc Natl Acad Sci U S A 103(5):1422-7 PMID 16432237
- ^ Lee YD, et al. (2008) Dif1 is a DNA-damage-regulated facilitator of nuclear import for ribonucleotide reductase. Mol Cell 32(1):70-80 PMID 18851834
- ^ Lowdon M and Vitols E (1973) Ribonucleotide reductase activity during the cell cycle of Saccharomyces cerevisiae. Arch Biochem Biophys 158(1):177-84 PMID 4580840
- ^ Lee YD and Elledge SJ (2006) Control of ribonucleotide reductase localization through an anchoring mechanism involving Wtm1. Genes Dev 20(3):334-44 PMID 16452505
- ^ Rittberg DA and Wright JA (1989) Relationships between sensitivity to hydroxyurea and 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIO) and ribonucleotide reductase RNR2 mRNA levels in strains of Saccharomyces cerevisiae. Biochem Cell Biol 67(7):352-7 PMID 2675933
- ^ Chabes A, et al. (2000) Yeast ribonucleotide reductase has a heterodimeric iron-radical-containing subunit. Proc Natl Acad Sci U S A 97(6):2474-9 PMID 10716984
- ^ Elledge SJ and Davis RW (1987) Identification and isolation of the gene encoding the small subunit of ribonucleotide reductase from Saccharomyces cerevisiae: DNA damage-inducible gene required for mitotic viability. Mol Cell Biol 7(8):2783-93 PMID 3313004
- ^ Sommerhalter M, et al. (2004) Structures of the yeast ribonucleotide reductase Rnr2 and Rnr4 homodimers. Biochemistry 43(24):7736-42 PMID 15196016
- ^ Basso TS, et al. (2008) Low productivity of ribonucleotide reductase in Saccharomyces cerevisiae increases sensitivity to stannous chloride. Genet Mol Res 7(1):1-6 PMID 18273813
- ^ Xu H, et al. (2006) Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly. Proc Natl Acad Sci U S A 103(11):4028-33 PMID 16537480
- ^ Wang PJ, et al. (1997) Rnr4p, a novel ribonucleotide reductase small-subunit protein. Mol Cell Biol 17(10):6114-21 PMID 9315671
- ^ Zhou Z and Elledge SJ (1992) Isolation of crt mutants constitutive for transcription of the DNA damage inducible gene RNR3 in Saccharomyces cerevisiae. Genetics 131(4):851-66 PMID 1516817
- ^ Domkin V, et al. (2002) Yeast DNA damage-inducible Rnr3 has a very low catalytic activity strongly stimulated after the formation of a cross-talking Rnr1/Rnr3 complex. J Biol Chem 277(21):18574-8 PMID 11893751
- ^ Shen C, et al. (2007) TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol 27(20):7007-17 PMID 17698581
- ^ Li B and Reese JC (2001) Ssn6-Tup1 regulates RNR3 by positioning nucleosomes and affecting the chromatin structure at the upstream repression sequence. J Biol Chem 276(36):33788-97 PMID 11448965
- ^ Huang M and Elledge SJ (1997) Identification of RNR4, encoding a second essential small subunit of ribonucleotide reductase in Saccharomyces cerevisiae. Mol Cell Biol 17(10):6105-13 PMID 9315670
- ^ Strauss M, et al. (2007) RNR4 mutant alleles pso3-1 and rnr4Delta block induced mutation in Saccharomyces cerevisiae. Curr Genet 51(4):221-31 PMID 17287963
- ^ Elledge SJ, et al. (1993) DNA damage and cell cycle regulation of ribonucleotide reductase. Bioessays 15(5):333-9 PMID 8343143
- ^ Yoo SC, et al. (2009) Rice virescent3 and stripe1 encoding the large and small subunits of ribonucleotide reductase are required for chloroplast biogenesis during early leaf development. Plant Physiol 150(1):388-401 PMID 19297585
- ^ Elledge SJ, et al. (1992) Ribonucleotide reductase: regulation, regulation, regulation. Trends Biochem Sci 17(3):119-23 PMID 1412696
- ^ Abid MR, et al. (1999) Translational regulation of ribonucleotide reductase by eukaryotic initiation factor 4E links protein synthesis to the control of DNA replication. J Biol Chem 274(50):35991-8 PMID 10585489
- ^ Xu H, et al. (2008) The structural basis for peptidomimetic inhibition of eukaryotic ribonucleotide reductase: a conformationally flexible pharmacophore. J Med Chem 51(15):4653-9 PMID 18610997
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