Abstract
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 (MRE11ASM), causes skipping of a highly conserved exon while preserving the protein’s open reading frame. A new mouse model expressing Mre11ASM from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the MRE11ATLD1 mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11ASM is mislocalized to the cytoplasm, in contrast to MRE11ATLD1, which remains nuclear. Strikingly, MRE11ASM 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.
Highlights
Inherited deficiency in the ability of cells to respond to DNA damage leads to instability of the genome
Whereas AT patients are usually asymptomatic at birth and develop degeneration of the cerebellum later, Nijmegen breakage syndrome (NBS) patients are commonly born with microcephaly and manifest severe developmental delays
ataxia-telangiectasia-like disorder (ATLD) results from a diverse group of MRE11 mutations that are spread throughout the protein[10]
Summary
Inherited deficiency in the ability of cells to respond to DNA damage leads to instability of the genome. Syndromes resulting from defective DSB responses feature diverse sequelae such as cancer, immunodeficiency, neurodegeneration and developmental delay[1]. ATM phosphorylates proteins in local chromatin to affect large-scale changes that provide a scaffold for assembly of higher-order complexes that protect, process, and repair the DNA4. These events occur with remarkable speed, and can be detected within 15 seconds of experimentally-induced damage[3]. Several patients diagnosed clinically with AT, displaying cerebellar degeneration, cellular hypersensitivity to ionizing radiation (IR), and chromosome instability, were found to have no alteration in ATM DNA sequence or protein expression This lead to the disease name ataxia-telangiectasia-like disorder (ATLD) (MIM 604391). One was a nonsense mutation (R633X) that deletes 78 amino acids from the C-terminus (Fig. 1b), while the other was a missense mutation in the N-terminal nuclease domain (N117S)[11]
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