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MRE11
MRE11 double strand break repair nuclease
The MRE11 gene provides instructions for a protein critical in DNA double-strand break repair, maintaining genomic stability and preventing serious cellular damage. The MRE11 gene encodes the MRE11 double strand break repair nuclease protein, a key component of the MRE11-RAD50-NBN (MRN) complex.
MRE11 is located on the long (q) arm of chromosome 11, at band 11q21. Arm ratio per GRCh38 - banding schematic.
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Overview
The MRE11 gene, officially known as MRE11 double strand break repair nuclease, is fundamental to maintaining the integrity of the human genome. It produces a protein that acts as a nuclease, an enzyme capable of cutting nucleic acids. This MRE11 protein is a crucial subunit of the MRE11-RAD50-NBN (MRN) complex, a molecular machine that senses and repairs DNA double-strand breaks.
These double-strand breaks are severe forms of DNA damage that can arise from various sources, including ionising radiation, certain chemicals, or errors during DNA replication. Without efficient repair, such damage can lead to chromosomal rearrangements, cell death, or uncontrolled cell growth, contributing to conditions like cancer. The MRE11 protein's role in this process underscores its importance for cellular function and disease prevention.
What the gene does
The MRE11 protein is a central component of the multi-protein MRE11-RAD50-NBN (MRN) complex, which functions as a primary sensor and effector of DNA double-strand breaks. This complex is rapidly recruited to sites of DNA damage, where it initiates several critical repair pathways.
Specifically, MRE11 possesses both exonuclease and endonuclease activities. Its exonuclease activity allows it to trim DNA ends, which is important for processing damaged DNA before repair can occur. The endonuclease activity helps in creating nicks or cuts within DNA strands. Beyond its enzymatic roles, MRE11 also acts as a scaffold, helping to bring other repair proteins to the site of damage and coordinate the intricate steps of DNA repair. This includes activating cell cycle checkpoints to halt cell division, thereby preventing the replication of damaged DNA, and facilitating homologous recombination and non-homologous end-joining pathways to mend the breaks.
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Chromosome location
The MRE11 gene is situated on the long arm of chromosome 11, specifically at position 11q21. Chromosomes are organised structures of DNA found within cells, and each chromosome has a distinct location. The 'q' denotes the long arm, while '21' refers to the specific band on that arm. This precise location helps in mapping and understanding the genetic context of MRE11.
Protein structure
The MRE11 protein is composed of 708 amino acids and exhibits a modular structure essential for its various functions. A key region involved in protein-protein interactions is located between amino acids 87 and 117, facilitating its interaction with the NBN protein, another vital component of the MRN complex. Additionally, the protein contains several intrinsically disordered regions. These include a region from amino acids 507 to 540, another from 556 to 614, and a third at the C-terminus, from amino acids 651 to 708. Within one of these disordered segments, specifically from amino acids 570 to 594, a Glycine-Arginine-rich (GAR) motif is present, which may be involved in specific binding or regulatory functions.
Key variants
Genetic variations, or variants, in the MRE11 gene can alter the function of the MRE11 protein. These changes may range from single nucleotide polymorphisms (SNPs) to larger deletions or insertions within the gene sequence. Depending on their nature and location, MRE11 variants can impair the protein's ability to participate in DNA repair pathways, leading to genomic instability. The clinical impact of these variants varies considerably, from benign to pathogenic, and can influence an individual's susceptibility to certain health conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1096C>T | p.Arg366Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
c.1127del | p.Phe376fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
c.1378G>T | p.Glu460Ter | Pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
c.1441dup | p.Thr481fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1458_1461del | p.Lys486fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder 1 |
c.1532dup | p.Asn511fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.163_167del | p.Ile55fs | Pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
c.490_496dup | p.Pro166delinsHisTer | Pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
c.784del | p.Tyr262fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.939del | p.Val313_Leu314insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Ataxia-telangiectasia-like disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
While specific conditions are not listed as directly caused by MRE11 variants in this context, the gene's critical role in DNA repair suggests that disruptions could contribute to conditions associated with genomic instability. Disorders linked to impaired DNA repair often involve an increased risk of cancer, neurodevelopmental issues, or premature ageing syndromes. Research into conditions potentially associated with MRE11 variants is ongoing, focusing on how compromised DNA repair mechanisms manifest in human health.
No disease links recorded for this gene in our reference set.
UK clinical status
In the UK, the MRE11 gene is assessed on several NHS England Genomic Medicine Service approved panels through PanelApp. These include panels for Ataxia and cerebellar anomalies in childhood onset, DDG2P (a panel for developmental disorders), Dystonia, chorea or related movement disorder in childhood onset, Hereditary ataxia, and Hereditary ataxia of adult onset. This indicates that MRE11 variants are considered relevant for diagnostic screening in individuals presenting with these neurological conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the MRE11 gene responsible for?
The MRE11 gene provides instructions for creating a protein that is a crucial part of the MRE11-RAD50-NBN (MRN) complex. This complex is primarily responsible for detecting and repairing DNA double-strand breaks, which are severe forms of DNA damage.
What happens if the MRE11 gene doesn't work correctly?
If the MRE11 gene does not function properly, it can lead to impaired DNA repair. This can result in genomic instability, meaning the cell's DNA is more prone to damage and errors, potentially increasing the risk for certain health conditions associated with DNA repair defects.
How is MRE11 relevant to human health?
MRE11's role in DNA repair is vital for maintaining healthy cells and preventing disease. Dysfunctional MRE11 can impact genomic stability, which is broadly linked to conditions involving cellular damage and uncontrolled cell growth. Its inclusion on NHS diagnostic panels for various neurological conditions underscores its clinical significance.