Disease relevance of MRE11

• Structural and functional similarities between the SbcCD proteins of Escherichia coli and the RAD50 and MRE11 (RAD32) recombination and repair proteins of yeast [1].

High impact information on MRE11

• The Mre11 nuclease and the ATM-related Tel1 kinase are the first proteins detected at DSBs [2].
• The cellular response to DSBs and DNA replication stress is likely directed by the Mre11 complex detecting and processing DNA ends in conjunction with Sae2 and by RP-A recognizing single-stranded DNA and recruiting additional checkpoint and repair proteins [2].
• Unlike the response to DSBs, Mre11 and recombination proteins are not recruited to hydroxyurea-stalled replication forks unless the forks collapse [2].
• Mre11 forms a complex with Rad50 and Xrs2, acting as the binding core, and participates in DSB processing [3].
• Mre11 repairs methyl methanesulfonate-induced DSBs by reactions that require the nuclease activities and those that do not [3].

Biological context of MRE11

• Recombination-induced CAG trinucleotide repeat expansions in yeast involve the MRE11-RAD50-XRS2 complex [4].
• MRE11 functions in several aspects of DNA metabolism, including meiotic recombination, double-strand break repair, and telomere maintenance [5].
• Transcripts of the MRE11 gene increased transiently and showed the same kinetics as that of the RAD50 gene during meiosis [6].
• We cloned the MRE11 gene and found that it encodes a 643-amino acid protein with a highly acidic region containing a heptad repeat of Asp at its C-terminus and is located downstream of YMR44 near the RNA1 locus on the right arm of chromosome XIII [6].
• This genetic interaction was independent of Mre11 nuclease activity but was dependent on a DNA repair function [7].

Anatomical context of MRE11

• Conditionally, MRE11 null chicken DT40 cells accumulate chromosome breaks and die upon Mre11 repression, showing frequent centrosome amplification [8].
• The MRE11 gene has previously been implicated in DSB repair in the yeast Saccharomyces cerevisiae . Here we have developed a methodology to study the roles of the murine Mre11 homolog in pluripotent embryonic stem cells [9].

Associations of MRE11 with chemical compounds

• The MRE11, RAD50, and XRS2 genes of Saccharomyces cerevisiae are involved in the repair of DNA double-strand breaks (DSBs) produced by ionizing radiation and by radiomimetic chemicals such as methyl methanesulfonate (MMS) [10].
• By contrast, the mre11 mutant is sensitive to damage to DNA by methyl methanesulfonate and exhibits a hyperrecombination phenotype in mitosis [11].
• At all of the targeted residues, alanine substitution resulted in a more severe defect in DNA repair compared to the more conservative asparagine substitutions, but all of the mutant proteins exhibited <2% of the exonuclease activity observed for wild-type Mre11 [12].
• The isolation and characterization of an alkylating-agent-sensitive yeast mutant, ngs1 [13].
• Extracts of ngs1 and NGS1+ strains contained approximately equal levels of an activity that removes 3-methyladenine (3MA) and 7-methylguanine (7MG) from DNA in vitro [13].

Physical interactions of MRE11

• Using a two-hybrid system, we found that Mre11 interacts with Rad50 and itself in vivo [6].
• Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway [14].
• However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1 [14].
• However, domains in Xrs2p located both 49 amino acids upstream and 104 amino acids downstream of the Mre11p binding site are required for meiotic recombination and telomere elongation, respectively, in addition to the 32-amino acid region [15].

Regulatory relationships of MRE11

• The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction [14].
• The Saccharomyces cerevisiae MRE11 gene is required for the repair of ionizing radiation-induced DNA damage and for the initiation of meiotic recombination [16].
• DSB end processing induced by HO endonuclease was suppressed in both mre11-58 and the mre11 disruption mutant [17].
• These endonuclease activities of Mre11 are enhanced markedly by Rad50 but only in the presence of ATP [18].
• Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination [15].

Other interactions of MRE11

• The type 1 mutations (mre2 and mre11) confer a reduction in MNase sensitivity relative to the wild-type level [19].
• This suggests that other nucleases can compensate for loss of the Exo1 and Mre11 nucleases, but not of the Mre11-Rad50-Xrs2 complex [5].
• RAD58 (XRS4)--a new gene in the RAD52 epistasis group [20].
• The mre2 and mre11 deletion mutants are proficient in mitotic recombination, but are defective in meiotic recombination and in formation of viable spores [21].
• The mre11-H125N mutation, which eliminates the nuclease activities of Mre11, causes an accumulation of unprocessed double-strand breaks (DSBs) in meiosis, but no defect in processing HO-induced DSBs in mitotic cells, suggesting the existence of redundant activities [5].

Analytical, diagnostic and therapeutic context of MRE11

• Using complementation tests and nucleotide sequencing, we showed that the rad58-4 mutation was an allele of the MRE11 gene and have renamed the mutation mre11-58 [17].
• Using a gene targeting approach, a triple LoxP site cassette was inserted into a region of MRE11 genomic DNA flanking conserved phosphodiesterase motifs [9].
• Here, we use chromatin immunoprecipitation (ChIP) to determine if Mre11p, Tel1p, or Mec1p affects telomere maintenance by promoting recruitment of telomerase subunits to S. cerevisiae telomeres [22].
• We report here a structural analysis of full-length S. cerevisiae Rad50, alone and in a complex with yeast Mre11 by electron microscopy [23].
• Molecular cloning and sequencing of NGS1 as a putative DNA-alkylation repair gene revealed that it isidentical to MRE11, a gene that is involved in DNA recombinational repair [24].

References