CancerQuest >> Closer Look >> DNA Damaging Agents

Mechanisms of Alkylating Agents

Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

In the first mechanism an alkylating agent (represented in the figure below as a pink star) attaches alkyl groups (small carbon compounds-depicted as pink triangles) to DNA bases. This alteration results in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases (frame 3 of the diagram below). Alkylated bases prevent DNA synthesis and RNA transcription from the affected DNA.

A second mechanism by which alkylating agents cause DNA damage is the formation of cross-bridges, bonds between atoms in the DNA (pink linkages below). In this process, two bases are linked together by an alkylating agent that has two DNA binding sites. Bridges can be formed within a single molecule of DNA (as shown below) or a cross-bridge may connect two different DNA molecules. Cross-linking prevents DNA from being separated for synthesis or transcription.

The third mechanism of action of alkylating agents is the induction of mispairing of the nucleotides leading to mutations. In a normal DNA double helix, A always pairs with (is across from) T and G always pairs with C. As the figure below shows, alkylated G bases may erroneously pair with Ts. If this altered pairing is not corrected it may lead to a permanent mutation.