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A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability.

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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Xiao H,Yu Z,Wu Y,Nan J,Merry DE,Sekiguchi JM,Ferguson DO,Lieberman AP,Dressler GR

doi

10.1093/hmg/dds246

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

4225-36

issue

19

eissn

0964-6906

issn

1460-2083

pii

dds246

journal_volume

21

pub_type

杂志文章

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