Freudenreich Catherine H
Department of Biology and Program in Genetics, Tufts University, Medford, MA 02155, USA.
Front Biosci. 2007 Sep 1;12:4911-24. doi: 10.2741/2437.
Fragile Sites are regions of genomes that are prone to breakage. In human cells, rare fragile sites are due to expansion of repetitive sequences which have been either shown or predicted to form DNA secondary structures such as hairpins, cruciforms, and quadruplexes. For human common fragile sites, which are components of normal chromatin structure, are induced by replication inhibitors, and encompass much larger regions (100s-1000s of kilobases) it has been more difficult to define particular sequence elements responsible for fragility. However recent progress reviewed here in understanding the link between replication and fragility, as well as identification of proteins and conditions needed to prevent chromosome fragility, have shed some light onto the reasons for breakage at common fragile sites. In addition, the discovery of several types of natural fragile sites on yeast chromosomes and the characterization of associated deletions, duplications, and translocations, has revealed potential mechanisms for fragility and for the chromosomal rearrangements that follow. An understanding of these events will provide insight into the generation of cancer, since deletions and rearrangements at human common fragile sites and associated tumor suppressor genes are an early event in tumorigenesis.
脆性位点是基因组中易于断裂的区域。在人类细胞中，罕见脆性位点是由于重复序列的扩增所致，这些重复序列已被证明或预测会形成诸如发夹、十字形和四链体等DNA二级结构。对于人类常见脆性位点，它们是正常染色质结构的组成部分，由复制抑制剂诱导产生，且包含大得多的区域（数百至数千千碱基），因此更难确定导致脆性的特定序列元件。然而，本文回顾的关于理解复制与脆性之间联系的最新进展，以及对防止染色体脆性所需蛋白质和条件的鉴定，已为常见脆性位点断裂的原因提供了一些线索。此外，酵母染色体上几种天然脆性位点的发现以及相关缺失、重复和易位的特征描述，揭示了脆性以及后续染色体重排的潜在机制。对这些事件的理解将有助于深入了解癌症的发生，因为人类常见脆性位点及相关肿瘤抑制基因的缺失和重排是肿瘤发生的早期事件。
