1. Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.
- Author
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Hartlerode AJ, Mostafa AM, Orban SK, Benedeck R, Campbell K, Hoenerhoff MJ, Ferguson DO, and Sekiguchi JM
- Subjects
- Animals, Mice, Humans, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Disease Models, Animal, Nuclear Proteins genetics, Nuclear Proteins metabolism, DNA Breaks, Double-Stranded, MRE11 Homologue Protein genetics, MRE11 Homologue Protein metabolism, Ataxia Telangiectasia genetics, Ataxia Telangiectasia metabolism, Ataxia Telangiectasia pathology, Ataxia Telangiectasia Mutated Proteins genetics, Ataxia Telangiectasia Mutated Proteins metabolism, Phenotype, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, DNA Repair genetics, Mice, Transgenic
- 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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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