Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes

Abstract

The MRE11 DNA nuclease plays central roles in the repair of DNA double-strand breaks (DSBs) as a core component of the MRE11-RAD50-NBS1 (MRN) complex. MRN localizes to chromosomal DSBs and recruits and activates the DSB repair protein kinase, ATM, which phosphorylates downstream substrates to elicit cellular DNA damage responses. Pathogenic variants in MRE11 cause the genome instability disorder ataxia-telangiectasia-like disorder (ATLD). The first ATLD patient allele identified, ATLD1, is a nonsense mutation that deletes 76 residues from the MRE11 C-terminus and markedly reduces levels of MRE11-ATLD1 and the entire MRN complex. The MRE11 C-terminus has been demonstrated to function in DNA binding, mediate protein interactions, and undergo post-translational modifications that regulate the MRE11 nuclease. We previously demonstrated that transgenic mice expressing reduced wildtype MRN levels exhibit severe phenotypes, including small body size, anemia, and DNA DSB repair defects. Thus, it is currently unknown whether low MRE11-ATLD1 levels, loss of the C-terminus, or both cause disease-associated phenotypes. In this study, we generated transgenic mouse models that express near endogenous or significantly reduced levels of MRE11-ATLD1 to determine the in vivo importance of the MRE11 C-terminus. We observe that low MRE11-ATLD1 expression leads to anemia, bone marrow failure, extramedullary hematopoiesis, and impaired lymphocyte development, similar to mice expressing low wildtype MRE11. In contrast, higher MRE11-ATLD1 expression results in a subset of moderate phenotypes, indicating that loss of the C-terminus has limited impact on MRN functions in vivo. These findings provide a foundation for predicting the clinical presentation and severity of ATLD patient phenotypes.

Keywords: DNA repair; genome instability; hematopoiesis; lymphocyte development.