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MRE11A

MRE11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMRE11, ATLD, HNGS1, MRE11B, MRE11A, MRE11 homolog A, double strand break repair nuclease, MRE11 homolog, double strand break repair nuclease
External IDsOMIM: 600814; MGI: 1100512; HomoloGene: 4083; GeneCards: MRE11; OMA:MRE11 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005590
NM_005591
NM_001330347

NM_018736
NM_001310728

RefSeq (protein)

NP_001317276
NP_005581
NP_005582

NP_001297657
NP_061206

Location (UCSC)Chr 11: 94.42 – 94.49 MbChr 9: 14.7 – 14.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Double-strand break repair protein MRE11 (Meiotic recombination 11) is an enzyme that in humans is encoded by the MRE11 gene.[5] The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.

Function

This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[6]

Orthologs

Mre11, an ortholog of human MRE11, occurs in the prokaryote archaeon Sulfolobus acidocaldarius.[7] In this organism the Mre11 protein interacts with the Rad50 protein and appears to have an active role in the repair of DNA damages experimentally introduced by gamma radiation.[7] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks,[8] by a process that likely involves homologous recombination. These observations suggest that human MRE11 is descended from prokaryotic and protist ancestral Mre11 proteins that served a role in early processes for repairing DNA damage.

Overexpression in cancer

MRE11 has a role in microhomology-mediated end joining (MMEJ) repair of double strand breaks. It is one of 6 enzymes required for this error prone DNA repair pathway.[9] MRE11 is over-expressed in breast cancers.[10]

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[citation needed] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[citation needed] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damages which, through replication errors (translesion synthesis), lead to mutations and cancer. However, MRE11 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Interactions

MRE11 has been shown to interact with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000020922Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031928Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR, Weaver DT (September 1995). "Isolation and characterization of the human MRE11 homologue". Genomics. 29 (1): 80–6. doi:10.1006/geno.1995.1217. PMID 8530104.
  6. ^ "Entrez Gene: MRE11 MRE11 meiotic recombination 11 homolog A (S. cerevisiae)".
  7. ^ a b Quaiser A, Constantinesco F, White MF, Forterre P, Elie C (February 2008). "The Mre11 protein interacts with both Rad50 and the HerA bipolar helicase and is recruited to DNA following gamma irradiation in the archaeon Sulfolobus acidocaldarius". BMC Molecular Biology. 9: 25. doi:10.1186/1471-2199-9-25. PMC 2288612. PMID 18294364.
  8. ^ Lukaszewicz A, Howard-Till RA, Novatchkova M, Mochizuki K, Loidl J (October 2010). "MRE11 and COM1/SAE2 are required for double-strand break repair and efficient chromosome pairing during meiosis of the protist Tetrahymena". Chromosoma. 119 (5): 505–18. doi:10.1007/s00412-010-0274-9. PMID 20422424. S2CID 12642689.
  9. ^ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (March 2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death & Disease. 6 (3): e1697. doi:10.1038/cddis.2015.58. PMC 4385936. PMID 25789972.
  10. ^ Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S (October 2012). "Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer". Journal of the National Cancer Institute. 104 (19): 1485–502. doi:10.1093/jnci/djs355. PMID 22914783.
  11. ^ Kim ST, Lim DS, Canman CE, Kastan MB (December 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". The Journal of Biological Chemistry. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
  12. ^ a b c d Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes & Development. 14 (8): 927–39. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.
  13. ^ a b Chiba N, Parvin JD (October 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". The Journal of Biological Chemistry. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724.
  14. ^ Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M (May 2001). "Direct DNA binding by Brca1". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6086–91. doi:10.1073/pnas.111125998. PMC 33426. PMID 11353843.
  15. ^ Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, et al. (July 1999). "Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response". Science. 285 (5428): 747–50. doi:10.1126/science.285.5428.747. PMID 10426999.
  16. ^ a b Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (October 1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nature Genetics. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516. S2CID 13443404.
  17. ^ Xu X, Stern DF (October 2003). "NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors". FASEB Journal. 17 (13): 1842–8. doi:10.1096/fj.03-0310com. PMID 14519663. S2CID 24870579.
  18. ^ a b Trujillo KM, Yuan SS, Lee EY, Sung P (August 1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". The Journal of Biological Chemistry. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271.
  19. ^ Cerosaletti KM, Concannon P (June 2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". The Journal of Biological Chemistry. 278 (24): 21944–51. doi:10.1074/jbc.M211689200. PMID 12679336.
  20. ^ Matsuzaki K, Shinohara A, Shinohara M (May 2008). "Forkhead-associated domain of yeast Xrs2, a homolog of human Nbs1, promotes nonhomologous end joining through interaction with a ligase IV partner protein, Lif1". Genetics. 179 (1): 213–25. doi:10.1534/genetics.107.079236. PMC 2390601. PMID 18458108.
  21. ^ Desai-Mehta A, Cerosaletti KM, Concannon P (March 2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Molecular and Cellular Biology. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.
  22. ^ Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH (September 1996). "Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair". Molecular and Cellular Biology. 16 (9): 4832–41. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.
  23. ^ Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (July 2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nature Genetics. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888. S2CID 6689794.

Further reading