RRM2B explained

Ribonucleotide-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the RRM2B gene.^{[1] [2] [3] [4]} The gene encoding the RRM2B protein is located on chromosome 8, at position 8q23.1. The gene and its products are also known by designations MTDPS8A, MTDPS8B, and p53R2.

Function

RRM2B codes for one of two versions of the R2 subunit of ribonucleotide reductase, which generates nucleotide precursors required for DNA replication by reducing ribonucleoside diphosphates to deoxyribonucloside diphosphates. The version of R2 encoded by RRM2B is induced by p53, and is required for normal DNA repair and mtDNA synthesis in non-proliferating cells. The other form of R2 is expressed only in dividing cells.^[5]

Interactions

RRM2B has been shown to interact with Mdm2^[6] and Ataxia telangiectasia mutated.^[6]

Clinical relevance

Abnormalities in this gene are one of the causes of mitochondrial DNA depletion syndrome (MDDS).^{[7] [8]} Neonatal hypotonia, developmental delay, encephalopathy, with seizures, deafness and lactic acidosis have been associated with mutations in this gene. MDDS is fatal, with death occurring from respiratory failure in early childhood.^{[9] [10]}

It has been associated with some cases of pediatric acute liver failure.^[11]

Mutations in this gene have been shown to cause progressive external ophthalmoplegia.^[12]

Increased expression of RRM2B has been correlated with gemcitabine resistance in human cholangiocarcinoma cells^[13] and may be predictive of lack of clinical benefit from gemcitabine for human cancers.

Further reading

• Guittet O, Håkansson P, Voevodskaya N, Fridd S, Gräslund A, Arakawa H, Nakamura Y, Thelander L . Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells . The Journal of Biological Chemistry . 276 . 44 . 40647–51 . November 2001 . 11517226 . 10.1074/jbc.M106088200 . free .
• Yamaguchi T, Matsuda K, Sagiya Y, Iwadate M, Fujino MA, Nakamura Y, Arakawa H . p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint . Cancer Research . 61 . 22 . 8256–62 . November 2001 . 11719458 .
• Yanamoto S, Kawasaki G, Yoshitomi I, Mizuno A . Expression of p53R2, newly p53 target in oral normal epithelium, epithelial dysplasia and squamous cell carcinoma . Cancer Letters . 190 . 2 . 233–43 . February 2003 . 12565178 . 10.1016/S0304-3835(02)00588-8 .
• Xue L, Zhou B, Liu X, Qiu W, Jin Z, Yen Y . Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits . Cancer Research . 63 . 5 . 980–6 . March 2003 . 12615712 .
• Zhou B, Liu X, Mo X, Xue L, Darwish D, Qiu W, Shih J, Hwu EB, Luh F, Yen Y . The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53 . Cancer Research . 63 . 20 . 6583–94 . October 2003 . 14583450 .
• Shao J, Zhou B, Zhu L, Qiu W, Yuan YC, Xi B, Yen Y . In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase . Cancer Research . 64 . 1 . 1–6 . January 2004 . 14729598 . 10.1158/0008-5472.CAN-03-3048 . free .
• Ceballos E, Muñoz-Alonso MJ, Berwanger B, Acosta JC, Hernández R, Krause M, Hartmann O, Eilers M, León J . Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes . Oncogene . 24 . 28 . 4559–71 . June 2005 . 15856024 . 10.1038/sj.onc.1208652 . 21190604 .
• Deng ZL, Xie DW, Bostick RM, Miao XJ, Gong YL, Zhang JH, Wargovich MJ . Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls . World Journal of Gastroenterology . 11 . 33 . 5169–73 . September 2005 . 16127747 . 4320390 . 10.3748/wjg.v11.i33.5169 . 31 January 2024 . free.
• Ohno K, Tanaka-Azuma Y, Yoneda Y, Yamada T . Genotoxicity test system based on p53R2 gene expression in human cells: examination with 80 chemicals . Mutation Research . 588 . 1 . 47–57 . December 2005 . 16236544 . 10.1016/j.mrgentox.2005.09.002 .
• Qiu W, Zhou B, Darwish D, Shao J, Yen Y . Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits . Biochemical and Biophysical Research Communications . 340 . 2 . 428–34 . February 2006 . 16376858 . 10.1016/j.bbrc.2005.12.019 .
• Okumura H, Natsugoe S, Yokomakura N, Kita Y, Matsumoto M, Uchikado Y, Setoyama T, Owaki T, Ishigami S, Aikou T . Expression of p53R2 is related to prognosis in patients with esophageal squamous cell carcinoma . Clinical Cancer Research . 12 . 12 . 3740–5 . June 2006 . 16778101 . 10.1158/1078-0432.CCR-05-2416 . 15106205 .
• Yen Y, Chu B, Yen C, Shih J, Zhou B . Enzymatic property analysis of p53R2 subunit of human ribonucleotide reductase . Advances in Enzyme Regulation . 46 . 235–47 . 2007 . 16846634 . 10.1016/j.advenzreg.2006.01.016 .
• Lembo D, Donalisio M, Cornaglia M, Azzimonti B, Demurtas A, Landolfo S . Effect of high-risk human papillomavirus oncoproteins on p53R2 gene expression after DNA damage . Virus Research . 122 . 1–2 . 189–93 . December 2006 . 16872707 . 10.1016/j.virusres.2006.06.011 .
• Yokomakura N, Natsugoe S, Okumura H, Ikeda R, Uchikado Y, Mataki Y, Takatori H, Matsumoto M, Owaki T, Ishigami S, Aikou T . Improvement in radiosensitivity using small interfering RNA targeting p53R2 in esophageal squamous cell carcinoma . Oncology Reports . 18 . 3 . 561–7 . September 2007 . 17671702 . 10.3892/or.18.3.561 . free .

Notes and References

1. Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y, Nakamura Y . A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage . Nature . 404 . 6773 . 42–9 . March 2000 . 10716435 . 10.1038/35003506 . 2000Natur.404...42T . 4327888 .
2. Nakano K, Bálint E, Ashcroft M, Vousden KH . A ribonucleotide reductase gene is a transcriptional target of p53 and p73 . Oncogene . 19 . 37 . 4283–9 . August 2000 . 10980602 . 10.1038/sj.onc.1203774 . free .
3. Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chrétien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rötig A . Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion . Nature Genetics . 39 . 6 . 776–80 . June 2007 . 17486094 . 10.1038/ng2040 . 22103978 .
4. Web site: Entrez Gene: RRM2B ribonucleotide reductase M2 B (TP53 inducible).
5. Copeland WC . Defects in mitochondrial DNA replication and human disease . Critical Reviews in Biochemistry and Molecular Biology . 47 . 1 . 64–74 . 2012 . 22176657 . 3244805 . 10.3109/10409238.2011.632763 .
6. Chang L, Zhou B, Hu S, Guo R, Liu X, Jones SN, Yen Y . ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage . Proceedings of the National Academy of Sciences of the United States of America . 105 . 47 . 18519–24 . November 2008 . 19015526 . 2587585 . 10.1073/pnas.0803313105 . 2008PNAS..10518519C . free .
7. Book: Gorman. Gráinne S.. Taylor. Robert W. . vanc . GeneReviews. April 17, 2014. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK195854/. RRM2B-Related Mitochondrial Disease. 24741716.
8. Web site: RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy. United States National Library of Medicine. 13 July 2017.
9. Acham-Roschitz B, Plecko B, Lindbichler F, Bittner R, Mache CJ, Sperl W, Mayr JA . A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy . Molecular Genetics and Metabolism . 98 . 3 . 300–4 . November 2009 . 19616983 . 10.1016/j.ymgme.2009.06.012 .
10. Kropach N, Shkalim-Zemer V, Orenstein N, Scheuerman O, Straussberg R . Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature . Neuropediatrics . May 2017 . 28482374 . 10.1055/s-0037-1601867 . 48 . 6 . 456–462. 7809119 .
11. Valencia CA, Wang X, Wang J, Peters A, Simmons JR, Moran MC, Mathur A, Husami A, Qian Y, Sheridan R, Bove KE, Witte D, Huang T, Miethke AG . Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism . PLOS ONE . 11 . 8 . e0156738 . 2016 . 27483465 . 10.1371/journal.pone.0156738 . 4970743. 2016PLoSO..1156738V . free .
12. Takata A, Kato M, Nakamura M, Yoshikawa T, Kanba S, Sano A, Kato T . Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia . Genome Biology . 12 . 9 . R92 . September 2011 . 21951382 . 3308055 . 10.1186/gb-2011-12-9-r92 . free .
13. Sato J, Kimura T, Saito T, Anazawa T, Kenjo A, Sato Y, Tsuchiya T, Gotoh M . Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma . Journal of Hepato-Biliary-Pancreatic Sciences . 18 . 5 . 700–11 . September 2011 . 21451941 . 10.1007/s00534-011-0376-7 . 19975519 .