MRE11A Protein

title: MRE11A Protein
description: MRE11A protein page for NeuroWiki

MRE11A Protein

Introduction

Mre11A Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [@suberbielle2015]

<div class="infobox infobox-protein"> [@rodriguez2011]
<table> [@yuan2012]
<tr><th colspan="2" style="background:#e65100; color:white;">MRE11A</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Double-strand break repair protein MRE11A</td></tr>
<tr><td><strong>Gene</strong></td><td>[MRE11](/genes/mre11)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P43146](https://www.uniprot.org/uniprot/P43146)</td></tr>
<tr><td><strong>PDB IDs</strong></td><td>1L8D, 3T8Y, 5U6T</td></tr>
<tr><td><strong>Molecular Weight</td><td>80 kDa (708 amino acids)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (nuclear foci)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>MRE11 nuclease family</td></tr>
<tr><td><strong>Aliases</strong></td><td>MRE11, MRE11A, HNGS1, ATLD</td></tr>
</table>
</div>

Overview

...

title: MRE11A Protein
description: MRE11A protein page for NeuroWiki

MRE11A Protein

Introduction

Mre11A Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes. [@suberbielle2015]

<div class="infobox infobox-protein"> [@rodriguez2011]
<table> [@yuan2012]
<tr><th colspan="2" style="background:#e65100; color:white;">MRE11A</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Double-strand break repair protein MRE11A</td></tr>
<tr><td><strong>Gene</strong></td><td>[MRE11](/genes/mre11)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P43146](https://www.uniprot.org/uniprot/P43146)</td></tr>
<tr><td><strong>PDB IDs</strong></td><td>1L8D, 3T8Y, 5U6T</td></tr>
<tr><td><strong>Molecular Weight</td><td>80 kDa (708 amino acids)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (nuclear foci)</td></tr>
<tr><td><strong>Protein Family</strong></td><td>MRE11 nuclease family</td></tr>
<tr><td><strong>Aliases</strong></td><td>MRE11, MRE11A, HNGS1, ATLD</td></tr>
</table>
</div>

Overview

MRE11A (Meiotic Recombination 11 Homolog A) is a critical nuclease enzyme involved in the recognition, processing, and repair of DNA double-strand breaks (DSBs) [1]. As the core component of the MRN complex (MRE11-RAD50-NBS1), MRE11A plays an essential role in maintaining genomic stability through its involvement in both homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways [2]. The protein possesses unique nuclease activities that allow it to process DNA ends, resect broken DNA, and initiate the DNA damage response signaling cascade. MRE11A is evolutionarily conserved from yeast to humans, reflecting its fundamental importance in DNA metabolism [3].

In the nervous system, MRE11A is particularly important due to the post-mitotic nature of [neurons](/entities/neurons), which cannot replicate to fix DNA damage through cell division. Mutations in MRE11A cause Ataxia-Telangiectasia-Like Disease (ATLD), a rare autosomal recessive disorder characterized by cerebellar degeneration, ataxia, and increased cancer predisposition [4]. Furthermore, dysfunction of MRE11A and the MRN complex has been implicated in the pathogenesis of Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions, where DNA damage accumulation contributes to neuronal dysfunction and death [5][6].

Structure

Domain Architecture

MRE11A contains several distinct structural domains:

• N-terminal Nuclease Domain (residues 1-300): Contains the HD-domain phosphodiesterase motifs responsible for nuclease activity
• DNA Binding Domain (residues 300-450): Binds double-stranded DNA ends and hairpins
• C-terminal Domain (residues 450-600): Mediates protein-protein interactions
• Rad50 Binding Domain (residues 600-708): Essential for forming the MRN complex with RAD50

Structural Features

• Nuclease Active Site: Contains conserved histidine-aspartate (HD) motif for metal-dependent hydrolysis
• Dimerization Interface: Forms homodimers through C-terminal interactions
• DNA End Recognition: Bends and unwinds DNA at damage sites
• NBS1 Interaction Surface: Recruits NBS1 for ATM activation

Three-Dimensional Structure

Crystal structures reveal:

• Nuclease domain fold: Similar to the calcineurin-like phosphodiesterases
• DNA binding groove: Positively charged channel for DNA engagement
• Dimer arrangement: Antiparrallel dimerization creating dual DNA binding sites

Post-Translational Modifications

• Phosphorylation: ATM phosphorylates MRE11A at Ser676 and Ser678 in response to DNA damage [7]
• SUMOylation: SUMO modification affects nuclear foci formation
• Acetylation: Regulates nuclease activity and protein stability

Normal Function

Nuclease Activity

MRE11A possesses unique enzymatic properties:

Endonuclease Activity: Cleaves DNA internally at damage sites, creating single-strand breaks

3'→5' Exonuclease Activity: Progressively removes nucleotides from DNA ends

Hairpin Opening: Resolves secondary structures and hairpin loops

DNA End Processing: Prepares DNA ends for repair by removing damaged nucleotides

MRN Complex Function

As the defining component of the MRN complex, MRE11A:

• Damage Recognition: Rapidly localizes to DNA double-strand break sites
• DNA End Bridging: Brings together broken DNA ends through dimerization
• ATM Recruitment: Directly activates ATM kinase signaling
• End Resection: Initiates 5'→3' DNA end resection for homologous recombination

DNA Repair Pathways

MRE11A participates in multiple DNA repair mechanisms:

Homologous Recombination (HR)

• DNA end resection (with EXO1 and BLM)

-ssDNA overhang generation

• RAD51 loading facilitation
• Repair synthesis coordination

Non-Homologous End Joining (NHEJ)

• DNA end processing
• Ligation fidelity improvement
• Microhomology utilization

Alternative End Joining

• Backup pathway when classical NHEJ fails
• Increased mutagenic potential

Tissue-Specific Functions

In the nervous system, MRE11A supports:

• Neuronal DNA Repair: Critical for maintaining neuronal genome integrity
• V(D)J Recombination: Development of immune repertoire
• Genomic Stability: Preventing accumulation of mutations in long-lived neurons

Role in Neurodegenerative Diseases

Ataxia-Telangiectasia-Like Disease (ATLD)

ATLD is caused by biallelic pathogenic variants in MRE11A [4]:

Genetics

• Autosomal recessive inheritance
• Over 30 pathogenic variants identified
• Missense and truncating mutations

Pathogenesis

• Partial loss of nuclease function
• Impaired MRN complex assembly
• Reduced ATM activation
• Accumulation of unrepaired DNA damage

Clinical Features

• Progressive cerebellar ataxia (childhood onset)
• Oculomotor apraxia
• Mild immunodeficiency
• Increased cancer predisposition (hematological malignancies)
• Elevated alpha-fetoprotein
• Radiation sensitivity

Alzheimer's Disease

MRE11A dysfunction contributes to AD pathogenesis [5]:

DNA Damage Accumulation

• Elevated DNA double-strand breaks in AD neurons
• Impaired recruitment of repair proteins to damage sites
• Reduced MRE11A nuclear foci formation

Pathological Interactions

• [Amyloid-beta](/proteins/amyloid-beta) induces DNA damage in neurons
• [Tau](/proteins/tau) pathology impairs DNA repair responses
• Mitochondrial dysfunction exacerbates nuclear DNA damage

Therapeutic Implications

• Enhancing MRE11A function may protect neurons
• Gene therapy approaches under investigation

Parkinson's Disease

MRE11A involvement in PD includes [6]:

Dopaminergic Neuron Vulnerability

• High metabolic demand increases [ROS](/entities/reactive-oxygen-species)-induced DNA damage
• Reduced DNA repair capacity in substantia nigra neurons
• Age-related decline in MRE11A function

Alpha-Synuclein Interaction

• Pathological [alpha-synuclein](/proteins/alpha-synuclein) may impair DNA repair
• MRE11A mislocalization in PD brain

Amyotrophic Lateral Sclerosis (ALS)

• DNA repair deficits in motor neurons
• Impaired response to oxidative DNA damage
• [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology affects DNA repair gene expression

Therapeutic Approaches

Targeting MRE11A for neuroprotection:

• Small Molecule Activators: Compounds enhancing MRE11A nuclease activity
• Gene Therapy: Viral vector-mediated MRE11A expression
• Combination Approaches: Enhancing multiple DNA repair proteins
• ATM Inhibitors: Synthetic lethal approaches

Expression Pattern

Tissue Distribution

• High expression: Testis, thymus, spleen (high proliferative activity)
• Moderate expression: Brain, heart, muscle
• Low expression: Most differentiated tissues

Cellular Localization

• Nuclear localization: Predominantly nuclear
• DNA damage foci: Rapid recruitment to damage sites
• Cytoplasmic pool: Minor cytoplasmic fraction

Brain Expression

• Neurons: High expression in cortical and hippocampal neurons
• Glia: Moderate expression in [astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation)
• Subcellular: Nuclear and perinuclear regions

Interactions

Protein-Protein Interactions

• RAD50: Core component of MRN complex
• NBS1 (NBN): Essential for ATM activation
• ATM: Kinase phosphorylated in response to DNA damage
• BRCA1: Cooperative roles in homologous recombination
• CtIP: Promotes DNA end resection

Nucleic Acid Interactions

• Double-stranded DNA: Primary substrate
• Single-stranded DNA: Generated during DNA end resection
• DNA hairpins: Processed during V(D)J recombination

See Also

• [MRE11 Gene](/genes/mre11)
• [Ataxia-Telangiectasia-Like Disease](/diseases/ataxia-telangiectasia-like-disease)
• [DNA Repair Mechanisms](/mechanisms/dna-repair-neurodegeneration)mechanisms/dna-repair-neurodegeneration)
• [MRN Complex](/tags/mrn-complex)
• [Nibrin Protein](/proteins/nibrin-protein)
• [RAD50 Protein](/proteins/rad50-protein)
• [ATM Protein](/proteins/atm-protein)
• [Neurodegeneration Pathways](/tags/neurodegeneration)

Background

The study of Mre11A Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [UniProt: MRE11A (P43146)](https://www.uniprot.org/uniprot/P43146)
• [NCBI Gene: MRE11](https://www.ncbi.nlm.nih.gov/gene/7326)
• [PDB: MRE11 structures](https://www.rcsb.org/structure/1L8D)
• [GeneReviews: ATLD](https://www.ncbi.nlm.nih.gov/books/NBK1155/)
• [Human Protein Atlas: MRE11A](https://www.proteinatlas.org/ENSG00000020916-MRE11)

References

[Hopfner KP, et al., (2001). Mre11Rad50 complex: an end resection machine for DNA repair. Science, 294(5540), 129-135 (2001)](https://doi.org/10.1126/science.1063523)

[Williams RS, et al., (2009). Mre11 nuclease activity has essential roles in DNA repair and genomic stability. Cell, 139(1), 87-99 (2009)](https://doi.org/10.1016/j.cell.2009.09.034)

[Unknown, Stracker TH, Petrini JH. (2011). The MRE11 complex: starting from the ends. Nature Reviews Molecular Cell Biology, 12(2), 90-103 (2011)](https://doi.org/10.1038/nrm3047)

[Taylor AM, et al., (2004). Ataxia-telangiectasia-like disorder. Handbook of Clinical Neurology, 83, 161-173 (2004)](https://doi.org/10.1016/S0072-9752(03)

[Suberbielle E, et al., (2015). DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications, 6, 8897 (2015)](https://doi.org/10.1038/ncomms9897)

[Rodriguez M, et al., (2011). DNA repair in Parkinson's disease. Parkinson's Disease, 2011, 287619 (2011)](https://doi.org/10.4061/2011/287619)

[Yuan SS, et al., (2012). ATM-mediated phosphorylation of MRE11. DNA Repair, 11(4), 405-415 (2012)](https://doi.org/10.1016/j.dnarep.2012.01.003)