Chatterjee Nimrat, Lin Yunfu, Wilson John H
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Postdoc J. 2016 May;4(5):46-54. doi: 10.14304/surya.jpr.v4n5.1.
Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology. Recently, we showed that activated ATR is the major signal for convergent-transcription-induced cell death at CAG repeats and is regulated by the mismatch repair (MMR) pathway. Additionally, components of other DNA repair pathways such as transcription-coupled nucleotide excision repair (TC-NER) and R-loop resolution by RNaseH reduce cell death. Because activated ATR signals the Fanconi anemia (FA) pathway of interstrand crosslink DNA repair, we asked whether the FA pathway also modulates convergent-transcription-induced cell death at expanded CAG repeats. We show here that siRNA knockdown of FA components-FANCI, FANCJ, FANCM, FANCA, and FANCD2-decreases cell death, suggesting that FA proteins, like MMR proteins, are activators of cell death during convergent transcription.
近20种无法治愈的神经退行性疾病是由三核苷酸重复序列（TNR）扩展超过一定阈值引起的，疾病的发病时间和严重程度与重复序列长度呈正相关。通常，长TNRs倾向于进一步扩展，重复序列不仅在从亲代到子代的种系传递过程中继续扩展，而且在患者的体细胞组织中也保持高度不稳定。因此，了解TNR不稳定机制有助于揭示潜在的疾病病理。最近，我们发现激活的ATR是CAG重复序列处转录趋同诱导细胞死亡的主要信号，并且受错配修复（MMR）途径调控。此外，其他DNA修复途径的成分，如转录偶联核苷酸切除修复（TC-NER）和通过RNaseH解决R环，可减少细胞死亡。由于激活的ATR为链间交联DNA修复的范可尼贫血（FA）途径发出信号，我们询问FA途径是否也调节扩展的CAG重复序列处转录趋同诱导的细胞死亡。我们在此表明，对FA成分FANCI、FANCJ、FANCM、FANCA和FANCD2进行siRNA敲低可减少细胞死亡，这表明FA蛋白与MMR蛋白一样，是转录趋同过程中细胞死亡的激活因子。
