MRE11A
Double-strand break repair protein MRE11A is a protein that in humans is encoded by the MRE11A gene.[5]
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 MRE11A, 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 MRE11A 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
MRE11A has been shown to interact with:
- ATM,[11][12]
- BRCA1,[12][13][14][15]
- Ku70,[16]
- MDC1,[17]
- NBN,[12][18][19][20][21]
- Rad50,[12][13][16][18][22] and
- TERF2.[23]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000020922 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031928 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR, Weaver DT (February 1996). "Isolation and characterization of the human MRE11 homologue". Genomics. 29 (1): 80–6. doi:10.1006/geno.1995.1217. PMID 8530104.
- ^ "Entrez Gene: MRE11A MRE11 meiotic recombination 11 homolog A (S. cerevisiae)".
- ^ a b Quaiser A, Constantinesco F, White MF, Forterre P, Elie C (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 Mol. Biol. 9: 25. doi:10.1186/1471-2199-9-25. PMC 2288612. PMID 18294364.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ 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.
- ^ Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis. 6 (3): e1697. doi:10.1038/cddis.2015.58. PMC 4385936. PMID 25789972.
- ^ Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ, Lo S (2012). "Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer". J. Natl. Cancer Inst. 104 (19): 1485–502. doi:10.1093/jnci/djs355. PMID 22914783.
- ^ Kim ST, Lim DS, Canman CE, Kastan MB (1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
- ^ a b c d Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927 (inactive 2020-01-22). PMC 316544. PMID 10783165.
{{cite journal}}: CS1 maint: DOI inactive as of January 2020 (link) - ^ a b Chiba N, Parvin JD (2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724.
- ^ Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M (2001). "Direct DNA binding by Brca1". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6086–91. doi:10.1073/pnas.111125998. PMC 33426. PMID 11353843.
- ^ Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH (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.
- ^ a b Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C (1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nat. Genet. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516.
- ^ Xu X, Stern DF (2003). "NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors". FASEB J. 17 (13): 1842–8. doi:10.1096/fj.03-0310com. PMID 14519663.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Trujillo KM, Yuan SS, Lee EY, Sung P (1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271.
- ^ Cerosaletti KM, Concannon P (2003). "Nibrin forkhead-associated domain and breast cancer C-terminal domain are both required for nuclear focus formation and phosphorylation". J. Biol. Chem. 278 (24): 21944–51. doi:10.1074/jbc.M211689200. PMID 12679336.
- ^ Matsuzaki K, Shinohara A, Shinohara M (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.
- ^ Desai-Mehta A, Cerosaletti KM, Concannon P (2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.
- ^ Dolganov GM, Maser RS, Novikov A, Tosto L, Chong S, Bressan DA, Petrini JH (1996). "Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair". Mol. Cell. Biol. 16 (9): 4832–41. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.
- ^ Zhu XD, Küster B, Mann M, Petrini JH, de Lange T (2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888.
Further reading
- Dolganov GM, Maser RS, Novikov A, et al. (1996). "Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair". Mol. Cell. Biol. 16 (9): 4832–41. doi:10.1128/MCB.16.9.4832. PMC 231485. PMID 8756642.
- Carney JP, Maser RS, Olivares H, et al. (1998). "The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response". Cell. 93 (3): 477–86. doi:10.1016/S0092-8674(00)81175-7. PMID 9590181.
- Paull TT, Gellert M (1998). "The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks". Mol. Cell. 1 (7): 969–79. doi:10.1016/S1097-2765(00)80097-0. PMID 9651580.
- Trujillo KM, Yuan SS, Lee EY, Sung P (1998). "Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95". J. Biol. Chem. 273 (34): 21447–50. doi:10.1074/jbc.273.34.21447. PMID 9705271.
- Chamankhah M, Wei YF, Xiao W (1999). "Isolation of hMRE11B: failure to complement yeast mre11 defects due to species-specific protein interactions". Gene. 225 (1–2): 107–16. doi:10.1016/S0378-1119(98)00530-7. PMID 9931460.
- Zhong Q, Chen CF, Li S, et al. (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.
- Goedecke W, Eijpe M, Offenberg HH, et al. (1999). "Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis". Nat. Genet. 23 (2): 194–8. doi:10.1038/13821. PMID 10508516.
- Kim ST, Lim DS, Canman CE, Kastan MB (2000). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
- Stewart GS, Maser RS, Stankovic T, et al. (2000). "The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder". Cell. 99 (6): 577–87. doi:10.1016/S0092-8674(00)81547-0. PMID 10612394.
- Wang Y, Cortez D, Yazdi P, et al. (2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927 (inactive 2020-01-22). PMC 316544. PMID 10783165.
{{cite journal}}: CS1 maint: DOI inactive as of January 2020 (link) - Gatei M, Young D, Cerosaletti KM, et al. (2000). "ATM-dependent phosphorylation of nibrin in response to radiation exposure". Nat. Genet. 25 (1): 115–9. doi:10.1038/75508. PMID 10802669.
- Zhu XD, Küster B, Mann M, et al. (2000). "Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres". Nat. Genet. 25 (3): 347–52. doi:10.1038/77139. PMID 10888888.
- de Vries H, Rüegsegger U, Hübner W, et al. (2000). "Human pre-mRNA cleavage factor II(m) contains homologs of yeast proteins and bridges two other cleavage factors". EMBO J. 19 (21): 5895–904. doi:10.1093/emboj/19.21.5895. PMC 305781. PMID 11060040.
- Fukuda T, Sumiyoshi T, Takahashi M, et al. (2001). "Alterations of the double-strand break repair gene MRE11 in cancer". Cancer Res. 61 (1): 23–6. PMID 11196167.
- Desai-Mehta A, Cerosaletti KM, Concannon P (2001). "Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization". Mol. Cell. Biol. 21 (6): 2184–91. doi:10.1128/MCB.21.6.2184-2191.2001. PMC 86852. PMID 11238951.
- Paull TT, Cortez D, Bowers B, et al. (2001). "Direct DNA binding by Brca1". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6086–91. doi:10.1073/pnas.111125998. PMC 33426. PMID 11353843.
- Hopfner KP, Karcher A, Craig L, et al. (2001). "Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase". Cell. 105 (4): 473–85. doi:10.1016/S0092-8674(01)00335-X. PMID 11371344.
- Pitts SA, Kullar HS, Stankovic T, et al. (2001). "hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay". Hum. Mol. Genet. 10 (11): 1155–62. doi:10.1093/hmg/10.11.1155. PMID 11371508.
- Chiba N, Parvin JD (2001). "Redistribution of BRCA1 among four different protein complexes following replication blockage". J. Biol. Chem. 276 (42): 38549–54. doi:10.1074/jbc.M105227200. PMID 11504724.