Genetics, Gene Therapy & Genetic Disease
- Recruitment of Scc2/4 to double-strand breaks depends on γH2A and DNA end resection
DSB recruitment of the cohesin loader Scc2/4 relies on Tel1 and γH2A, but contrary to cohesin not on Mec1; binding emanates from the break site and depends on as well as coincides with end resection.
- Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin
Using cellular models of the ADTKD–SEC61A1 causing mutations V67G and T185A, this study reveals specific aberrations of protein transport and calcium homeostasis as a potential pathogenic mechanism.
- Rbfox1 is required for myofibril development and maintaining fiber type–specific isoform expression in Drosophila muscles
Rbfox1 is required for the development of both fibrillar and tubular muscle fibers in adult Drosophila and interacts with Bruno1 to define fiber type–specific patterns of alternative splicing.
- Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline
A TPP1 mutation known to cause telomere shortening and bone marrow failure in humans recapitulates telomere loss but results in severe germline defects in mice without impacting murine hematopoiesis.
- Activation of mitochondrial unfolded protein response protects against multiple exogenous stressors
This work highlights the importance of the mitochondrial unfolded protein response in allowing organisms to survive external stressors through up-regulation of other stress response pathways.
- INPP5K and Atlastin-1 maintain the nonuniform distribution of ER–plasma membrane contacts in neurons
CIL-1 and ATLN-1 maintain the balance between ER tubules and sheets and prevent invasion of cortical ER sheets into the axon, contributing to the non-uniform distribution of neuronal ER-PM contacts.
- Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation and DNA damage response
This work studies known and new ADPRHL2 mutations with different disease mechanisms overall indicating that loss of nuclear ARH3 alone is pathogenic via dysregulated nuclear ADP ribosylation.
- High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo
The TFAM-to-mtDNA ratio is critically important and must be maintained within a physiological range to allow normal mtDNA expression and prevent nucleoid hypercompaction in different mouse tissues.
- Paralogous synthetic lethality underlies genetic dependencies of the cancer-mutated gene STAG2
The context-dependency of genetic interactions of the cohesin gene STAG2, specifically STAG1 and the iron regulatory gene IREB2, are revealed by CRISPR-Cas9 screening in three different cellular backgrounds.
- Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice
This work highlights the importance of CNS transduction for treatment of neurological diseases, a finding with significant clinical implications considering the long-lasting effects of gene therapy.