RRM2B

RRM2B

RRM2B

Protein-coding gene in the species Homo sapiens

Ribonucleotide-diphosphate reductase subunit M2 B is an enzyme that in humans is encoded by the RRM2B gene.[5][6][7][8] 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.

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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.[9]

Interactions

RRM2B has been shown to interact with Mdm2[10] and Ataxia telangiectasia mutated.[10]

Clinical relevance

Abnormalities in this gene are one of the causes of mitochondrial DNA depletion syndrome (MDDS).[11][12] 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.[13][14]

It has been associated with some cases of pediatric acute liver failure.[15]

Mutations in this gene have been shown to cause progressive external ophthalmoplegia.[16]

Increased expression of RRM2B has been correlated with gemcitabine resistance in human cholangiocarcinoma cells[17] and may be predictive of lack of clinical benefit from gemcitabine for human cancers.

References

  1. [1]
    GRCh38: Ensembl release 89: ENSG00000048392 – Ensembl, May 2017
  2. [2]
    GRCm38: Ensembl release 89: ENSMUSG00000022292 – Ensembl, May 2017
  3. [3]
    "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. [4]
    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. [5]
    Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y, Nakamura Y (March 2000). "A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage". Nature. 404 (6773): 42–9. Bibcode:2000Natur.404...42T. doi:10.1038/35003506. PMID 10716435. S2CID 4327888.
  6. [6]
    Nakano K, Bálint E, Ashcroft M, Vousden KH (August 2000). "A ribonucleotide reductase gene is a transcriptional target of p53 and p73". Oncogene. 19 (37): 4283–9. doi:10.1038/sj.onc.1203774. PMID 10980602.
  7. [7]
    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 (June 2007). "Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion". Nature Genetics. 39 (6): 776–80. doi:10.1038/ng2040. PMID 17486094. S2CID 22103978.
  8. [8]
    "Entrez Gene: RRM2B ribonucleotide reductase M2 B (TP53 inducible)".
  9. [9]
    Copeland WC (2012). "Defects in mitochondrial DNA replication and human disease". Critical Reviews in Biochemistry and Molecular Biology. 47 (1): 64–74. doi:10.3109/10409238.2011.632763. PMC 3244805. PMID 22176657.
  10. [10]
    Chang L, Zhou B, Hu S, Guo R, Liu X, Jones SN, Yen Y (November 2008). "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. Bibcode:2008PNAS..10518519C. doi:10.1073/pnas.0803313105. PMC 2587585. PMID 19015526.
  11. [11]
    Gorman GS, Taylor RW (April 17, 2014). "RRM2B-Related Mitochondrial Disease". GeneReviews. University of Washington, Seattle. PMID 24741716.
  12. [12]
    "RRM2B-related mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy". United States National Library of Medicine. Retrieved 13 July 2017.
  13. [13]
    Acham-Roschitz B, Plecko B, Lindbichler F, Bittner R, Mache CJ, Sperl W, Mayr JA (November 2009). "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. doi:10.1016/j.ymgme.2009.06.012. PMID 19616983.
  14. [14]
    Kropach N, Shkalim-Zemer V, Orenstein N, Scheuerman O, Straussberg R (May 2017). "Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature". Neuropediatrics. 48 (6): 456–462. doi:10.1055/s-0037-1601867. PMID 28482374. S2CID 7809119.
  15. [15]
    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 (2016). "Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism". PLOS ONE. 11 (8): e0156738. Bibcode:2016PLoSO..1156738V. doi:10.1371/journal.pone.0156738. PMC 4970743. PMID 27483465.
  16. [16]
    Takata A, Kato M, Nakamura M, Yoshikawa T, Kanba S, Sano A, Kato T (September 2011). "Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia". Genome Biology. 12 (9): R92. doi:10.1186/gb-2011-12-9-r92. PMC 3308055. PMID 21951382.
  17. [17]
    Sato J, Kimura T, Saito T, Anazawa T, Kenjo A, Sato Y, Tsuchiya T, Gotoh M (September 2011). "Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma". Journal of Hepato-Biliary-Pancreatic Sciences. 18 (5): 700–11. doi:10.1007/s00534-011-0376-7. PMID 21451941. S2CID 19975519.

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