Is Fanconi's anaemia defective in a process essential to the repair of DNA cross links?

Abstract

FANCONI'S anaemia (FA) is a rare autosomal recessive disease of man, characterised by a progressive hypoplastic pancytopenia associated with diverse congenital anomalies^1,2, spontaneous chromosome breakage³ and predisposition to leukaemia and other cancers^4,5. Lymphocytes from FA patients were found to be excessively susceptible to chromosome breakage by di- or polyfunctional alkylating agents^6,7, 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 replication^8–12. 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.