MRE11

MRE11
National Center for Biotechnology Information, U.S. National Library of Medicine · Public domain · source
Name	MRE11
Organism	Homo sapiens
Gene	MRE11A
Length	~708–716 aa

MRE11 MRE11 is a eukaryotic nuclease component of a conserved protein complex involved in DNA double-strand break recognition and processing. It acts in concert with other factors to maintain genomic stability during replication, recombination, and cell-cycle checkpoints. MRE11 dysfunction is implicated in cancer predisposition, radiosensitivity syndromes, and defects in meiotic recombination.

Introduction

MRE11 functions as part of a multiprotein assembly that senses DNA damage and coordinates repair with signaling pathways activated by Ataxia telangiectasia mutated and ATM and Rad3-related. The protein was identified through genetic screens in Saccharomyces cerevisiae and biochemical purification from mammalian extracts alongside proteins discovered in studies of Bloom syndrome, Nijmegen breakage syndrome, and Werner syndrome. MRE11 is evolutionarily conserved from bacteria such as Escherichia coli through archaea like Sulfolobus solfataricus to eukaryotes including Drosophila melanogaster and Mus musculus, linking research across model systems from Xenopus laevis egg extracts to human cell lines like HeLa.

Structure and Biochemistry

MRE11 contains nuclease motifs and DNA-binding domains characterized by X-ray crystallography and cryo-electron microscopy performed in collaborations between groups at institutions including Max Planck Society and Cold Spring Harbor Laboratory. Structural studies revealed a dimerization interface and coordination of metal ions, with active site residues conserved across orthologs such as those in Bacillus subtilis and Thermus thermophilus. MRE11 associates with partner proteins via domains mapped using mass spectrometry at facilities like European Molecular Biology Laboratory and Lawrence Berkeley National Laboratory. The biochemical activities include 3' to 5' exonuclease and single-strand endonuclease functions, characterized in assays developed by researchers affiliated with Howard Hughes Medical Institute, National Institutes of Health, and laboratories at University of Cambridge and Harvard Medical School.

Cellular Functions and DNA Repair Roles

MRE11 operates within a complex that mediates homologous recombination, non-homologous end joining interactions, and microhomology-mediated end joining, processes studied in contexts such as meiotic recombination in Caenorhabditis elegans and mitotic repair in Schizosaccharomyces pombe. It collaborates with proteins including those encoded by RAD50, NBN, BRCA1, and BRCA2, and participates in activation of checkpoint kinases like CHK2 and CHK1. In replication stress responses examined in human cancer models such as MCF7, MRE11 aids stalled fork processing alongside factors like RECQL4, FANCD2, and PCNA. Its roles intersect with telomere maintenance pathways involving TRF2 and recombination-driven repair studied in cells from Bloom and Werner syndrome patients.

Regulation and Post-translational Modifications

MRE11 activity is modulated by post-translational modifications including phosphorylation by kinases such as ATM and acetylation by histone acetyltransferases related to Tip60. Ubiquitination and SUMOylation impacting complex stability have been reported in studies involving SCF complex components and SUMO pathway enzymes characterized at institutions like University of Oxford and Stanford University. Interaction with chromatin remodelers such as members of the SWI/SNF family and methyltransferases like SETD2 integrates MRE11 function with histone modification landscapes explored in epigenetics research across centers including Broad Institute.

Clinical Significance and Disease Associations

Germline and somatic alterations impacting MRE11 function are linked to radiation sensitivity, immunodeficiency phenotypes, and predisposition to cancers including breast cancer, colorectal cancer, and neuroblastoma. Tumor sequencing consortia like The Cancer Genome Atlas have reported mutations and copy-number changes correlated with prognosis and therapeutic response to agents such as platinum compounds and PARP inhibitors evaluated in trials at Memorial Sloan Kettering Cancer Center and Mayo Clinic. MRE11-centered pathways are targets for synthetic-lethality strategies alongside inhibitors of ATR and DNA-PKcs, with translational studies conducted by biotech firms and cooperative groups including European Organisation for Research and Treatment of Cancer.

Model Organism Studies and Experimental Tools

Genetic knockouts and hypomorphic alleles in Mus musculus recapitulate developmental defects, sterility, and cancer susceptibility, providing in vivo models used at centers like Jackson Laboratory and Wellcome Sanger Institute. Yeast genetics in Saccharomyces cerevisiae and Schizosaccharomyces pombe enabled dissection of recombination intermediates and checkpoint activation using classical genetics from groups including those at University of California, San Francisco. Biochemical reconstitution with recombinant proteins expressed in systems such as Escherichia coli and Sf9 insect cells, combined with single-molecule imaging performed at facilities like Harvard University and University of Illinois Urbana-Champaign, has elucidated mechanistic steps. Experimental tools include antibodies developed by vendors collaborating with labs at European Molecular Biology Laboratory, CRISPR/Cas9 gene-editing platforms popularized at Broad Institute, and high-throughput screens run through cores at Dana-Farber Cancer Institute.

Category:DNA repair proteins