A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability.
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.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Hong
H
Xiao
Zhigang
Z
Yu
Yipin
Y
Wu
John
J
Nan
Diane E
DE
Merry
JoAnn M
JM
Sekiguchi
David O
DO
Ferguson
Andrew P
AP
Lieberman
Gregory R
GR
Dressler
D000818:Animals; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C485876:PAXIP1 protein, human; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine