Is Fanconi's anaemia defective in a process essential to the repair of DNA cross links?
Is Fanconi's anaemia defective in a process essential to the repair of DNA cross links?
复制标题
范科尼贫血是否在修复 DNA 交联的重要过程中存在缺陷？
作者：
M. Sasaki
FANCONI贫血（FA）是一种罕见的男性常染色体隐性遗传病，其特征为进行性发育不良性全血细胞减少症，伴有多种先天性异常1，2，自发性染色体断裂3以及白血病和其他癌症的易感性4，5。发现FA患者的淋巴细胞对二或多官能烷化剂引起的染色体断裂过度敏感6，7，这被解释为FA细胞DNA修复缺陷的可能迹象7。为了寻找证据，我已经测试了FA患者的淋巴细胞的染色体反应单和双功能丝裂霉素在治疗时的细胞周期阶段，并发现FA细胞有一个特定的缺陷，在修复前畸变损伤诱导的双功能丝裂霉素的损伤可能是DNA链间型交联。该实验的基本原理是，如果DNA损伤未修复，则可能与半保守DNA复制过程中染色体畸变的形成有因果关系8 - 12。由于DNA损伤的修复是一个限速过程，因此在G1早期处理具有修复能力的细胞将在损伤在S期固定为染色体畸变之前留下更多的时间进行修复，因此将导致比G1至S过渡期间处理更少的染色体畸变。然而，在修复缺陷细胞中，G1期任何位置的处理诱导的DNA损伤都与染色体畸变的形成最大程度地相关。
FANCONI'S anaemia (FA) is a rare autosomal recessive disease of man, characterised by a progressive hypoplastic pancytopenia associated with diverse congenital anomalies1,2, spontaneous chromosome breakage3 and predisposition to leukaemia and other cancers4,5. Lymphocytes from FA patients were found to be excessively susceptible to chromosome breakage by di- or polyfunctional alkylating agents6,7, and this was interpreted as a possible indication of defective DNA repair of the FA cells7. Seeking evidence for this, I have tested lymphocytes from FA patients for their chromosome response to mono- and difunctional mitomycins in relation to the cell cycle phase at the time of treatment, and have found that FA cells have a specific defect in the repair of pre-aberration lesions induced by difunctional mitomycin; the lesions are possibly DNA cross links of the interstrand type. The rationale of this experiment was the knowledge that if damage to DNA is left unrepaired it can be linked causally to the formation of chromosome aberrations by a process that resides in semi conservative DNA replication8–12. Since the repair of DNA damage is a rate-limiting process, the treatment of repair-proficient cells in early G1 would leave more time for repair before the damage is fixed into chromosome aberrations during the S phase, and consequently would result in fewer chromosome aberrations than treatment during the transition from G1 to S. In the repair-deficient cells, however, DNA damage induced by treatment in any position of G1 would be linked maximally to the formation of chromosome aberrations.