Bryant P E
School of Biomedical Sciences, University of St. Andrews, St. Andrews KY16 9TS, Scotland, UK.
Mutat Res. 1998 Aug 3;404(1-2):107-11. doi: 10.1016/s0027-5107(98)00101-8.
Chromatid breaks are thought to result from DNA double-strand breaks (dsb) but the mechanisms are not yet understood. The early (but still prevailing) 'breakage-first' hypothesis fails to explain the large size of chromatid breaks; many of which are estimated to represent the apparent loss of between 15 and 45 Mbp (up to 30% of an average chromatid). The alternative 'exchange' hypothesis of Revell has potential for explaining the large sizes of deletions, but assumes the interaction of two lesions which therefore predicts a quadratic dependence of chromatid breaks on radiation dose. The exchange hypothesis is not tenable for mammalian cells since chromatid breaks are observed to be induced linearly with dose in both human and rodent cells. An alternative 'signal' model of chromatid breaks is outlined whereby a single dsb, occurring within a large looped chromatin domain, is signalled (possibly by molecules such as DNAPK or ATM protein) and triggers the cell to undergo a recombinational exchange, either within a chromatid or between sister chromatids. If incomplete, such recombinational exchanges would appear as chromatid breaks at metaphase. It is suggested that the large looped chromatin domains could be equivalent to one or more likely several replication 'factories' in which the DNA processing enzymes required for exchange formation would be located.
染色单体断裂被认为是由DNA双链断裂（dsb）引起的，但其机制尚不清楚。早期（但仍占主导地位）的“先断裂”假说是未能解释染色单体断裂的大尺寸；其中许多估计代表了15至45兆碱基对之间的明显缺失（高达平均染色单体的30%）。Revell的另一种“交换”假说有解释大尺寸缺失的潜力，但假设了两个损伤的相互作用，因此预测染色单体断裂与辐射剂量呈二次依赖关系。由于在人类和啮齿动物细胞中观察到染色单体断裂与剂量呈线性关系，所以交换假说对哺乳动物细胞来说是站不住脚的。本文概述了一种染色单体断裂的替代“信号”模型，即发生在大的环状染色质结构域内的单个dsb被发出信号（可能是由诸如DNA依赖性蛋白激酶或ATM蛋白等分子发出），并触发细胞进行染色单体内或姐妹染色单体之间的重组交换。如果不完整，这种重组交换在中期会表现为染色单体断裂。有人提出，大的环状染色质结构域可能等同于一个或更可能是几个复制“工厂”，其中将定位形成交换所需的DNA加工酶。
