Formation of the Cross-Link 1-[n³-Deoxycytidyl], 2-[n¹-Deoxyguanosinyl]-Ethane in DNA Treated with n, n̍-Bis(2-Chloroethyl)-N-Nitrosourea

The cross-linked dinucleoside, 1-[N³-deoxycytidyl], 2-[N¹-deoxyguanosinyl]ethane, has been isolated from DNA which has been exposed to N, N̍-bis(2-chloroethyl)-N-nitrosourea. It is probable that this structure is responsible for the interstrand cross-linking observed previously by physical methods. The modification is unique in that it cross-links DNA through two base-pairing positions and probably arises through the transfer of a chloroethyl group to one of the bases followed by a second reaction of this group with the other strand of DNA. Initial attack could be at the N³ position of deoxycytidine, the N¹ position of deoxyguanosine, or possibly the O⁶ position of deoxyguanosine. Attack at the O⁶ position of deoxyguanosine would require an internal cyclization with the N¹ position of deoxyguanosine before secondary reaction with the N³ position of deoxycytidine but would explain resistance to N, N̍-bis(2-chloroethyl)-N-nitrosourea in cells capable of removing substituents on the O⁶ position of guanine.