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Updated: Jun 23, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder
Andrea J Hartlerode1,2, Ahmed M Mostafa1,3, Steven K Orban1
1Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States.
Abstract:
The MRE11/RAD50/NBS1 (MRN) complex plays critical roles in cellular responses to DNA double-strand breaks. MRN is involved in end binding and processing, and it also induces cell cycle checkpoints by activating the ataxia-telangiectasia mutated (ATM) protein kinase. Hypomorphic pathogenic variants in the MRE11, RAD50, or NBS1 genes cause autosomal recessive genome instability syndromes featuring variable degrees of dwarfism, neurological defects, anemia, and cancer predisposition. Disease-associated MRN alleles include missense and nonsense variants, and many cause reduced protein levels of the entire MRN complex. However, the dramatic variability in the disease manifestation of MRN pathogenic variants is not understood. We sought to determine if low protein levels are a significant contributor to disease sequelae and therefore generated a transgenic murine model expressing MRE11 at low levels. These mice display dramatic phenotypes including small body size, severe anemia, and impaired DNA repair. We demonstrate that, distinct from ataxia telangiectasia-like disorder caused by MRE11 pathogenic missense or nonsense variants, mice and cultured cells expressing low MRE11 levels do not display the anticipated defects in ATM activation. Our findings indicate that ATM signaling can be supported by very low levels of the MRN complex and imply that defective ATM activation results from perturbation of MRN function caused by specific hypomorphic disease mutations. These distinct phenotypic outcomes underline the importance of understanding the impact of specific pathogenic MRE11 variants, which may help direct appropriate early surveillance for patients with these complicated disorders in a clinical setting.
Insights
Low MRE11 protein levels cause DNA repair defects and anemia, but not ATM signaling issues. Specific MRE11 mutations, not just low levels, disrupt ATM activation in genome instability syndromes.
Area of Science:
- Genetics and Molecular Biology
- Genomics and Gene Expression
- Cellular Biology
Background:
- The MRE11/RAD50/NBS1 (MRN) complex is crucial for DNA double-strand break repair and cell cycle checkpoint activation via ATM kinase.
- Pathogenic variants in MRN genes cause genome instability syndromes with variable clinical features, including dwarfism, neurological defects, anemia, and cancer.
- The reasons for the wide variability in disease manifestation among patients with MRN variants are not fully understood.
Purpose of the Study:
- To investigate whether reduced MRE11 protein levels contribute significantly to the clinical phenotypes observed in genome instability syndromes.
- To differentiate the effects of low MRE11 protein levels from the effects of specific hypomorphic mutations on cellular functions, particularly ATM activation.
Main Methods:
- Generation of a transgenic mouse model expressing reduced levels of MRE11.
- Phenotypic analysis of the MRN-deficient mice, including body size, anemia, and DNA repair capacity.
- Assessment of ATM activation in MRN-low mice and cultured cells compared to cells with specific MRN pathogenic variants.
Main Results:
- Mice with low MRE11 levels exhibited smaller body size, severe anemia, and impaired DNA repair.
- Unlike ataxia-telangiectasia-like disorder caused by specific MRE11 mutations, low MRE11 levels did not impair ATM activation.
- ATM signaling can be sustained even with very low levels of the MRN complex.
Conclusions:
- Reduced MRE11 protein levels lead to distinct phenotypes, primarily affecting DNA repair and causing anemia, without compromising ATM activation.
- Defective ATM activation in genome instability syndromes is likely caused by functional disruption of the MRN complex by specific mutations, rather than solely by reduced protein levels.
- Understanding the specific impact of pathogenic MRE11 variants is essential for predicting disease severity and guiding clinical surveillance for affected patients.
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