Lin Yunfu, Hubert Leroy, Wilson John H
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mol Carcinog. 2009 Apr;48(4):350-61. doi: 10.1002/mc.20488.
Triplet repeat expansion is the molecular basis for several human diseases. Intensive studies using systems in bacteria, yeast, flies, mammalian cells, and mice have provided important insights into the molecular processes that are responsible for mediating repeat instability. The age-dependent, ongoing repeat instability in somatic tissues, especially in terminally differentiated neurons, strongly suggests a robust role for pathways that are independent of DNA replication. Several genetic studies have indicated that transcription can play a critical role in repeat instability, potentially providing a basis for the instability observed in neurons. Transcription-induced repeat instability can be modulated by several DNA repair proteins, including those involved in mismatch repair (MMR) and transcription-coupled nucleotide excision repair (TC-NER). Though the mechanism is unclear, it is likely that transcription facilitates the formation of repeat-specific secondary structures, which act as intermediates to trigger DNA repair, eventually leading to changes in the length of the repeat tract. In addition, other processes associated with transcription can also modulate repeat instability, as shown in a variety of different systems. Overall, the mechanisms underlying repeat instability in humans are unexpectedly complicated. Because repeat-disease genes are widely expressed, transcription undoubtedly contributes to the repeat instability observed in many diseases, but it may be especially important in nondividing cells. Transcription-induced instability is likely to involve an extensive interplay not only of the core transcription machinery and DNA repair proteins, but also of proteins involved in chromatin remodeling, regulation of supercoiling, and removal of stalled RNA polymerases, as well as local DNA sequence effects.
三联体重复序列扩增是多种人类疾病的分子基础。利用细菌、酵母、果蝇、哺乳动物细胞和小鼠等系统进行的深入研究，为介导重复序列不稳定性的分子过程提供了重要见解。体细胞组织中，尤其是终末分化神经元中，与年龄相关的、持续存在的重复序列不稳定性，强烈表明存在独立于DNA复制的途径发挥着重要作用。多项遗传学研究表明，转录在重复序列不稳定性中可能起关键作用，这可能为在神经元中观察到的不稳定性提供了基础。转录诱导的重复序列不稳定性可由多种DNA修复蛋白调节，包括参与错配修复（MMR）和转录偶联核苷酸切除修复（TC-NER）的蛋白。尽管机制尚不清楚，但转录可能促进了重复序列特异性二级结构的形成，这些二级结构作为中间体触发DNA修复，最终导致重复序列长度的改变。此外，如在各种不同系统中所示，与转录相关的其他过程也可调节重复序列不稳定性。总体而言，人类重复序列不稳定性的潜在机制异常复杂。由于重复序列疾病相关基因广泛表达，转录无疑会导致许多疾病中观察到的重复序列不稳定性，但在非分裂细胞中可能尤为重要。转录诱导的不稳定性可能不仅涉及核心转录机制和DNA修复蛋白之间的广泛相互作用，还涉及参与染色质重塑、超螺旋调节、停滞RNA聚合酶清除的蛋白以及局部DNA序列效应。
