| First Author | Hartlerode AJ | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 10121 |
| PubMed ID | 29973640 | Mgi Jnum | J:268252 |
| Mgi Id | MGI:6271141 | Doi | 10.1038/s41598-018-28370-5 |
| Citation | Hartlerode AJ, et al. (2018) Reversible mislocalization of a disease-associated MRE11 splice variant product. Sci Rep 8(1):10121 |
| abstractText | Ataxia-telangiectasia (AT) and related disorders feature cancer predisposition, neurodegeneration, and immunodeficiency resulting from failure to respond to DNA damage. Hypomorphic mutations in MRE11 cause an AT-like disorder (ATLD) with variable clinical presentation. We have sought to understand how diverse MRE11 mutations may provide unique therapeutic opportunities, and potentially correlate with clinical variability. Here we have undertaken studies of an MRE11 splice site mutation that was found in two ATLD siblings that died of pulmonary adenocarcinoma at the young ages of 9 and 16. The mutation, termed MRE11 alternative splice mutation (MRE11(ASM)), causes skipping of a highly conserved exon while preserving the protein's open reading frame. A new mouse model expressing Mre11(ASM) from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the MRE11(ATLD1) mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11(ASM) is mislocalized to the cytoplasm, in contrast to MRE11(ATLD1), which remains nuclear. Strikingly, MRE11(ASM) mislocalization is corrected by inhibition of the proteasome, implying that the protein undergoes strict protein quality control in the nucleus. These findings raise the prospect that inhibition of poorly understood nuclear protein quality control mechanisms might have therapeutic benefit in genetic disorders causing cytoplasmic mislocalization. |
