Topoisomerase I mechanism

In the case of eukaryotic topoisomerase I, a single strand is attacked and a 3'-phosphotyrosyl linkage is formed. Religation takes place through attack of the 5' hydroxyl to the previously formed phosphate group (Fig. 7.8).

FIGURE 7.8 Transesterification reactions involved in topoisomerase I (topo I) activity.

FIGURE 7.8 Transesterification reactions involved in topoisomerase I (topo I) activity.

Binding site

1. Topoisomerase binding

2. Single strand nicking

Binding site

1. Topoisomerase binding

2. Single strand nicking

Topo l O-Tyr

Topo l O-Tyr

n coils

Cleavable complex fS

Rotation of free 5' end n-1 coils

Topo l

1. Religation

2. Enzyme dissociation Tyr—O 3

n-1 coils

FIGURE 7.9 Mechanism of DNA unwinding by topoisomerase I.

Topoisomerase I acts by making a transient break (nick) of a single strand of DNA, catalyzing the passage of DNA strands through one another and allowing release of the superhelical tension. Topoisomerase I enzymes have been sub-divided into type IA and type IB sub-families based on their reaction mechanism. Type I topoisomerases of the type IA sub-family form covalent linkages to the 5' end of the DNA break, while type IB sub-family enzymes form covalent linkages to the 3' end of DNA break (Fig. 7.9). Eukaryotic DNA topoisomerase I is attached to the 3' DNA end of the break site, and is therefore a type IB topoisomerase. This enzyme is located in areas of active RNA transcription to release superhelical stress generated during mRNA synthesis.

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