3'-TOP1 termini

FULL NAME: topoisomerase I linked 3'-end


DESCRIPTION:
The introduction of DNA single-strand breaks (nicks) by TOP1 provides swivel points that enable the rotation of the intact DNA strand around the break and facilitate DNA relaxation. The cleavage intermediate is referred to as a cleavage complex because TOP1 cleaves DNA by forming a covalent bond to the 3' DNA terminus that it generates. The covalently linked catalytic tyrosine of TOP1 (Y723 for human TOP1) is shown as the yellow circle. The first step of DNA relaxation by a TOP1 cleavage complex (TOP1cc) is a transesterification reaction whereby the catalytic tyrosine (Y723 for human TOP1) becomes linked to the 3' DNA end (nicking step). In the second step the torsional strain that results from DNA supercoiling drives the rotation of the 5' end of the nicked DNA strand around the intact strand. TOP1 encircles the rotating nicked DNA and slows its rotation. This process is referred to as 'controlled rotation'. In the last step the 5' end of the nicked DNA is realigned with the corresponding 3' end, which enables DNA religation (the closing step of the 'nicking–closing reaction'). TOP1ccs are normally transient because the closing step is much faster than the nicking step. Drugs and DNA lesions inhibit religation by misaligning the ends of the broken DNA. TOP1ccs can be stabilized under three conditions: - by drugs such as camptothecin, - by DNA lesions (damage) that misalign the 5' end of the nicked DNA, - by DNA and TOP1 modifications that occur during programmed cell death (apoptosis). Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3'-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (TOP1)-DNA covalent complexes. TDP1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolate and 3'-abasic sites, and exhibits 3'-nucleosidase activity indicating it may function as a general 3'-end-processing DNA repair enzyme.

DAMAGE TYPE: strand break


DNA DAMAGE SOURCE(S) (MAIN):
repair intermediate


DNA DAMAGE SOURCE(S) (MINOR):
cancer chemotherapy


DNA DAMAGE EFFECT(S) (MAIN):
apoptosis
cytotoxic


PATHWAYS:
base excision repair (BER)


DNA repair protein(s) related to damage:
TDP1


Last modification date: Oct. 10, 2011