Description | Both isoforms are approximately 80 kDa. Isoform 1 includes 708 amino acids; isoform 2 includes 680. Molecular studies of Mre11 typically do not distinguish between the different isoforms. Mre11 is a subunit of the Rad50/Mre11/NBS1 (R/M/N) complex and serves as a single-strand DNA endonuclease, a 3' to 5' DNA exonuclease, and to open hairpin DNA structures. |
Expression | All tissues examined, with higher levels in proliferating tissues. |
Localisation | Nuclear. |
Function | Mre11 participates in the repair of DNA double-strand breaks and replication errors as well as in meiotic homologous recombination. The R/M/N complex is part of the BRCA1-associated genome surveillance complex (BASC). The phosphorylation of Mre11 and NBS1 by another member of this super-complex, ATM, is essential for an early step in the response to DNA double-strand breaks (DSBs) and for their repair by either non-homologous end joining (NHEJ) or homologous recombination (HR). The interaction of DNA end-bound Mre11 with Ku70 may direct the break to rejoining by NHEJ, while the absense of Ku70 favors repair by HR. Current models propose DSB detection by R/M/N is required for the activation of ATM, which in turn phosphorylates Mre11 and NBS1, thus placing Mre11 both upstream and downstream of ATM in the DNA damage response signal transduction cascade. A mechanism has been proposed in which each end of a DNA DSB is bound by an R/M/N dimer, the two dimers being held to each other via the Zinc-hook domain of each Rad50 unit. As the Zinc-hook of Rad50 is located at the end of a long coiled-coil domain, this provides a flexible structure in which each DNA end is accessible to additional repair enzymes while being held in close proximity to each other in preparation for re-ligation. Cells lacking Mre11 are deficient in DSB repair, and exhibit hypersensitivity to DNA damaging agents such as ionizing radiation and radiomimetic drugs. Such cells also have abnormal DNA replication and high levels of chromosomal instability. |
Homology | The gene is conserved throughout eukaryotes, with 70% nucleic acid homology to S. cerevisiea Mre11. |
Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. |
Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M, Carroll D, Gautier J |
Molecular cell. 2001 ; 8 (1) : 137-147. |
PMID 11511367 |
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The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. |
Falck J, Petrini JH, Williams BR, Lukas J, Bartek J |
Nature genetics. 2002 ; 30 (3) : 290-294. |
PMID 11850621 |
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Alterations of the double-strand break repair gene MRE11 in cancer. |
Fukuda T, Sumiyoshi T, Takahashi M, Kataoka T, Asahara T, Inui H, Watatani M, Yasutomi M, Kamada N, Miyagawa K |
Cancer research. 2001 ; 61 (1) : 23-26. |
PMID 11196167 |
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Human MRE11 is inactivated in mismatch repair-deficient cancers. |
Giannini G, Ristori E, Cerignoli F, Rinaldi C, Zani M, Viel A, Ottini L, Crescenzi M, Martinotti S, Bignami M, Frati L, Screpanti I, Gulino A |
EMBO reports. 2002 ; 3 (3) : 248-254. |
PMID 11850399 |
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The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. |
Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA |
Nature. 2002 ; 418 (6897) : 562-566. |
PMID 12152085 |
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Isolation and characterization of the human MRE11 homologue. |
Petrini JH, Walsh ME, DiMare C, Chen XN, Korenberg JR, Weaver DT |
Genomics. 1995 ; 29 (1) : 80-86. |
PMID 8530104 |
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The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. |
Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM |
Cell. 1999 ; 99 (6) : 577-587. |
PMID 10612394 |
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BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. |
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J |
Genes & development. 2000 ; 14 (8) : 927-939. |
PMID 10783165 |
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