Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Hum Mol Genet. 2012 Oct 1;21(19):4225-36. doi: 10.1093/hmg/dds246. Epub 2012 Jun 26.
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.
谷氨酸（Q）扩展疾病是一组退行性疾病，由编码序列中似乎无关的基因中的 CAG 三核苷酸重复延长引起，其突变蛋白驱动发病机制。尽管有大量关于这些疾病遗传基础的分子证据，但突变多 Q 蛋白如何促进细胞死亡并驱动发病机制仍存在争议。在本报告中，我们显示了突变雄激素受体（AR）与核蛋白 PTIP（Pax 转录激活结构域相互作用蛋白）之间的特定相互作用，AR 是一种与脊髓和延髓肌肉萎缩症（SBMA）相关的蛋白质，PTIP 是一种具有异常长 Q 富含结构域的蛋白质，其功能是在 DNA 修复中。暴露于电离辐射后，PTIP 定位于核焦点，这是 DNA 损伤和修复的部位。然而，多 Q AR 的表达将 PTIP 从辐射诱导的核焦点中隔离出来。这导致对 DNA 损伤剂和染色体不稳定性的敏感性。在 SBMA 的小鼠模型中，在肌肉细胞核中检测到 DNA 损伤的证据，并且当去除编码 PTIP 的基因的一个拷贝时，肌肉萎缩加速。这些数据为理解在多 Q 扩展疾病中观察到的细胞退行性变的机制提供了新的范例。
