ArticleHuman molecular genetics2012
A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
- Molecular mechanisms underlying nucleotide repeat expansion disorders.Nature reviews. Molecular cell biology · 2021Review
- CAG RNAs induce DNA damage and apoptosis by silencingProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Deubiquitinase USP7 contributes to the pathogenicity of spinal and bulbar muscular atrophy.The Journal of clinical investigation · 2021Article
- Determining the Fate of Neurons in SCA3: ATX3, a Rising Decision Maker in Response to DNA Stresses and Beyond.Frontiers in cell and developmental biology · 2020Review
- Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in Spinal and Bulbar Muscular Atrophy.Scientific reports · 2019Article
- Expression of Human Endogenous Retrovirus-K in Spinal and Bulbar Muscular Atrophy.Frontiers in neurology · 2019Article
- The central role of DNA damage and repair in CAG repeat diseases.Disease models & mechanisms · 2018Review
- Mechanisms mediating spinal and bulbar muscular atrophy: investigations into polyglutamine-expanded androgen receptor function and dysfunction.Frontiers in neurology · 2013Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Glutamine (Q) expansion diseases are a family of degenerative disorders caused by the lengthening of CAG triplet repeats present in the coding sequences of seemingly unrelated genes whose mutant proteins drive pathogenesis. Despite all the molecular evidence for the genetic basis of these diseases, how mutant poly-Q proteins promote cell death and drive pathogenesis remains controversial. In this report, we show a specific interaction between the mutant androgen receptor (AR), a protein associated with spinal and bulbar muscular atrophy (SBMA), and the nuclear protein PTIP (Pax Transactivation-domain Interacting Protein), a protein with an unusually long Q-rich domain that functions in DNA repair. Upon exposure to ionizing radiation, PTIP localizes to nuclear foci that are sites of DNA damage and repair. However, the expression of poly-Q AR sequesters PTIP away from radiation-induced nuclear foci. This results in sensitivity to DNA-damaging agents and chromosomal instabilities. In a mouse model of SBMA, evidence for DNA damage is detected in muscle cell nuclei and muscular atrophy is accelerated when one copy of the gene encoding PTIP is removed. These data provide a new paradigm for understanding the mechanisms of cellular degeneration observed in poly-Q expansion diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.