RNR3

Ribosomna RNK 3, znana i kao RNR3, je ljudski gen. 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.https://www.yeastgenome.org/locus/RNR3

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.Elledge SJ and Davis RW (1990) Two genes differentially regulated in the cell cycle and by DNA-damaging agents encode alternative regulatory subunits of ribonucleotide reductase. Genes Dev 4(5):740-51 PMID 2199320Yao 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 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.Byrne KP and Wolfe KH (2005) The Yeast Gene Order Browser: combining curated homology and syntenic context reveals gene fate in polyploid species. Genome Res 15(10):1456-61 PMID 16169922Ge J, et al. (2001) Why multiple small subunits (Y2 and Y4) for yeast ribonucleotide reductase? Toward understanding the role of Y4. Proc Natl Acad Sci U S A 98(18):10067-72 PMID 11526232

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.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 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.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 20215435Wu 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 18838542Zhang 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

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.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 18851834Lowdon M and Vitols E (1973) Ribonucleotide reductase activity during the cell cycle of Saccharomyces cerevisiae. Arch Biochem Biophys 158(1):177-84 PMID 4580840Lee YD and Elledge SJ (2006) Control of ribonucleotide reductase localization through an anchoring mechanism involving Wtm1. Genes Dev 20(3):334-44 PMID 16452505Rittberg 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

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.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 10716984Elledge 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 3313004Sommerhalter M, et al. (2004) Structures of the yeast ribonucleotide reductase Rnr2 and Rnr4 homodimers. Biochemistry 43(24):7736-42 PMID 15196016 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).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 18273813Xu 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 16537480Wang PJ, et al. (1997) Rnr4p, a novel ribonucleotide reductase small-subunit protein. Mol Cell Biol 17(10):6114-21 PMID 9315671Zhou 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 1516817Domkin 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 11893751Shen 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 17698581Li 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 11448965Huang 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 9315670Strauss M, et al. (2007) RNR4 mutant alleles pso3-1 and rnr4Delta block induced mutation in Saccharomyces cerevisiae. Curr Genet 51(4):221-31 PMID 17287963Elledge 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 19297585Elledge SJ, et al. (1992) Ribonucleotide reductase: regulation, regulation, regulation. Trends Biochem Sci 17(3):119-23 PMID 1412696Abid 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 10585489Xu 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

Reference

Dopunska literatura

Nucleolus organizer regions are chromosomal regions crucial for the formation of the nucleolus, located on the short arms of the acrocentric chromosomes 13, 14, 15, 21 and 22

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