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MRE11A

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MRE11
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; GeneCards: MRE11
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

4361

17535

Ensembl

ENSG00000020922

ENSMUSG00000031928

UniProt

P49959

Q61216

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

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MRE11 functions as a member of the MRE11-RAD50-NBS1 (MRN) complex in mammals (or the MRE11-RAD50-XRS2 (MRX) complex in yeast). MRE11 is a DNA nuclease involved in multiple DNA double-strand break repair pathways, including homologous recombination,[6] classical non-homologous end joining,[7][8][9] and alternative non-homologous end joining.[7][8][9][10] MRE11 activity also facilitates replication fork restart[11][12] and telomere length maintenance. It also is essential for embryonic development[13][14] and required for hematopoiesis and lymphopoiesis in mice.[15] By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity, which is stimulated when complexed with RAD50.[16][17] CtIP/SAE2 is also known to stimulate MRE11 endonuclease activity to initiate homologous recombination[18][19][20] or to process blocked DNA ends, such as the removal of SPO11 during meiosis,[21][22] DNA-PKcs and Ku in mitotic cells,[23][24][25] or other DNA-protein adducts such as topoisomerase cleavage complexes.[26][27][28] In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short stretches of homology 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.[29]

Orthologs

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Mre11, an ortholog of human MRE11, occurs in the prokaryote archaeon Sulfolobus acidocaldarius.[30] 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.[30] Similarly, during meiosis in the eukaryotic protist Tetrahymena Mre11 is required for repair of DNA damages, in this case double-strand breaks,[31] 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

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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.[32] MRE11 is over-expressed in breast cancers.[33]

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

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MRE11 has been shown to interact with:

See also

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References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000020922 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031928 – Ensembl, 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): 80–86. doi:10.1006/geno.1995.1217. PMID 8530104.
  6. ↑ Ajimura M, Leem SH, Ogawa H (January 1993). "Identification of new genes required for meiotic recombination in Saccharomyces cerevisiae". Genetics. 133 (1): 51–66. doi:10.1093/genetics/133.1.51. PMC 1205298. PMID 8417989.
  7. 1 2 Rass E, Grabarz A, Plo I, Gautier J, Bertrand P, Lopez BS (August 2009). "Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells". Nature Structural & Molecular Biology. 16 (8). Nature Publishing Group: 819–824. doi:10.1038/nsmb.1641. PMID 19633668.
  8. 1 2 Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, Sekiguchi JM, et al. (August 2009). "Multiple functions of MRN in end-joining pathways during isotype class switching". Nature Structural & Molecular Biology. 16 (8). Nature Publishing Group: 808–813. doi:10.1038/nsmb.1639. PMC 2721910. PMID 19633670.
  9. 1 2 Xie A, Kwok A, Scully R (August 2009). "Role of mammalian Mre11 in classical and alternative nonhomologous end joining". Nature Structural & Molecular Biology. 16 (8). Nature Publishing Group: 814–818. doi:10.1038/nsmb.1640. PMC 2730592. PMID 19633669.
  10. ↑ Ma JL, Kim EM, Haber JE, Lee SE (December 2003). "Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences". Molecular and Cellular Biology. 23 (23): 8820–8828. doi:10.1128/MCB.23.23.8820-8828.2003. PMC 262689. PMID 14612421.
  11. ↑ Trenz K, Smith E, Smith S, Costanzo V (April 2006). "ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks". The EMBO Journal. 25 (8): 1764–1774. doi:10.1038/sj.emboj.7601045. PMC 1440833. PMID 16601701.
  12. ↑ Lemaçon D, Jackson J, Quinet A, Brickner JR, Li S, Yazinski S, et al. (October 2017). "MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells". Nature Communications. 8 (1) 860. Nature Publishing Group. doi:10.1038/s41467-017-01180-5. PMC 5643552. PMID 29038425.
  13. ↑ Xiao Y, Weaver DT (August 1997). "Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells". Nucleic Acids Research. 25 (15): 2985–2991. doi:10.1093/nar/25.15.2985. PMC 146850. PMID 9224597.
  14. ↑ Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, et al. (October 2008). "Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation". Cell. 135 (1): 85–96. doi:10.1016/j.cell.2008.08.015. PMC 2645868. PMID 18854157.
  15. ↑ DeFoer MB, Mostafa AM, Hartlerode AJ, Orban SK, McDonough K, Quirk S, et al. (November 2025). "Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes". Human Molecular Genetics. 34 (23): 1964–1978. doi:10.1093/hmg/ddaf154. PMC 13377461. PMID 41075274.
  16. ↑ Paull TT, Gellert M (June 1998). "The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks". Molecular Cell. 1 (7): 969–979. doi:10.1016/S1097-2765(00)80097-0. PMID 9651580.
  17. 1 2 3 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): 21447–21450. doi:10.1074/jbc.273.34.21447. PMID 9705271.
  18. ↑ Anand R, Ranjha L, Cannavo E, Cejka P (December 2016). "Phosphorylated CtIP Functions as a Co-factor of the MRE11-RAD50-NBS1 Endonuclease in DNA End Resection". Molecular Cell. 64 (5): 940–950. doi:10.1016/j.molcel.2016.10.017. PMID 27889449.
  19. ↑ Cannavo E, Cejka P (October 2014). "Sae2 promotes dsDNA endonuclease activity within Mre11-Rad50-Xrs2 to resect DNA breaks". Nature. 514 (7520). Nature Publishing Group: 122–125. doi:10.1038/nature13771. PMID 25231868.
  20. ↑ Deshpande RA, Lee JH, Arora S, Paull TT (November 2016). "Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts". Molecular Cell. 64 (3): 593–606. doi:10.1016/j.molcel.2016.10.010. PMID 27814491.
  21. ↑ Hartsuiker E, Mizuno K, Molnar M, Kohli J, Ohta K, Carr AM (April 2009). "Ctp1CtIP and Rad32Mre11 nuclease activity are required for Rec12Spo11 removal, but Rec12Spo11 removal is dispensable for other MRN-dependent meiotic functions". Molecular and Cellular Biology. 29 (7): 1671–1681. doi:10.1128/MCB.01182-08. PMC 2655602. PMID 19139281.
  22. ↑ Milman N, Higuchi E, Smith GR (November 2009). "Meiotic DNA double-strand break repair requires two nucleases, MRN and Ctp1, to produce a single size class of Rec12 (Spo11)-oligonucleotide complexes". Molecular and Cellular Biology. 29 (22). Taylor & Francis: 5998–6005. doi:10.1128/MCB.01127-09. PMC 2772569. PMID 19752195.
  23. ↑ Deshpande RA, Myler LR, Soniat MM, Makharashvili N, Lee L, Lees-Miller SP, et al. (January 2020). "DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP". Science Advances. 6 (2) eaay0922. American Association for the Advancement of Science. doi:10.1126/sciadv.aay0922. PMC 6949041. PMID 31934630.
  24. ↑ Reginato G, Cannavo E, Cejka P (December 2017). "Physiological protein blocks direct the Mre11-Rad50-Xrs2 and Sae2 nuclease complex to initiate DNA end resection". Genes & Development. 31 (23–24). Cold Spring Harbor Lab: 2325–2330. doi:10.1101/gad.308254.117. PMC 5795779. PMID 29321179.
  25. ↑ Wang W, Daley JM, Kwon Y, Krasner DS, Sung P (December 2017). "Plasticity of the Mre11-Rad50-Xrs2-Sae2 nuclease ensemble in the processing of DNA-bound obstacles". Genes & Development. 31 (23–24). Cold Spring Harbor Lab: 2331–2336. doi:10.1101/gad.307900.117. PMC 5795780. PMID 29321177.
  26. ↑ Aparicio T, Baer R, Gottesman M, Gautier J (February 2016). "MRN, CtIP, and BRCA1 mediate repair of topoisomerase II-DNA adducts". The Journal of Cell Biology. 212 (4): 399–408. doi:10.1083/jcb.201504005. PMC 4754713. PMID 26880199.
  27. ↑ Hoa NN, Shimizu T, Zhou ZW, Wang ZQ, Deshpande RA, Paull TT, et al. (November 2016). "Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes". Molecular Cell. 64 (3): 580–592. doi:10.1016/j.molcel.2016.10.011. PMID 27814490.
  28. ↑ Hartsuiker E, Neale MJ, Carr AM (January 2009). "Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA". Molecular Cell. 33 (1): 117–123. doi:10.1016/j.molcel.2008.11.021. PMC 2675033. PMID 19150433.
  29. ↑ "Entrez Gene: MRE11 MRE11 meiotic recombination 11 homolog A (S. cerevisiae)".
  30. 1 2 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.
  31. ↑ 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): 505–518. doi:10.1007/s00412-010-0274-9. PMID 20422424. S2CID 12642689.
  32. ↑ 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.
  33. ↑ Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, et al. (October 2012). "Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer". Journal of the National Cancer Institute. 104 (19): 1485–1502. doi:10.1093/jnci/djs355. PMID 22914783.
  34. ↑ 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): 37538–37543. doi:10.1074/jbc.274.53.37538. PMID 10608806.
  35. 1 2 3 4 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): 927–939. doi:10.1101/gad.14.8.927. PMC 316544. PMID 10783165.
  36. 1 2 Chiba N, Parvin JD (October 2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". The Journal of Biological Chemistry. 276 (42): 38549–38554. doi:10.1074/jbc.M105227200. PMID 11504724.
  37. ↑ 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): 6086–6091. doi:10.1073/pnas.111125998. PMC 33426. PMID 11353843.
  38. ↑ 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). New York, N.Y.: 747–750. doi:10.1126/science.285.5428.747. PMID 10426999.
  39. 1 2 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): 194–198. doi:10.1038/13821. PMID 10508516. S2CID 13443404.
  40. ↑ 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): 1842–1848. doi:10.1096/fj.03-0310com. PMID 14519663. S2CID 24870579.
  41. ↑ 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): 21944–21951. doi:10.1074/jbc.M211689200. PMID 12679336.
  42. ↑ 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): 213–225. doi:10.1534/genetics.107.079236. PMC 2390601. PMID 18458108.
  43. ↑ 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): 2184–2191. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.
  44. ↑ Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, et al. (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): 4832–4841. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.
  45. ↑ 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): 347–352. doi:10.1038/77139. PMID 10888888. S2CID 6689794.
  46. ↑ Nicolas Y, Bret H, Cannavo E, Acharya A, Cejka P, Borde V, et al. (June 2024). "Molecular insights into the activation of Mre11-Rad50 endonuclease activity by Sae2/CtIP". Molecular Cell. 84 (12): 2223–2237.e4. doi:10.1016/j.molcel.2024.05.019. PMID 38870937.
  47. ↑ Buis J, Stoneham T, Spehalski E, Ferguson DO (January 2012). "Mre11 regulates CtIP-dependent double-strand break repair by interaction with CDK2". Nature Structural & Molecular Biology. 19 (2). Nature Publishing Group: 246–252. doi:10.1038/nsmb.2212. PMC 3272152. PMID 22231403.
  48. ↑ Staples CJ, Barone G, Myers KN, Ganesh A, Gibbs-Seymour I, Patil AA, et al. (September 2016). "MRNIP/C5orf45 Interacts with the MRN Complex and Contributes to the DNA Damage Response". Cell Reports. 16 (10): 2565–2575. doi:10.1016/j.celrep.2016.07.087. PMC 5014761. PMID 27568553.

Further reading

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