Top1-PARP1 association and beyond: from DNA topology to break repair

Abstract

Selective trapping of human topoisomerase 1 (Top1) on the DNA (Top1 cleavage complexes; Top1cc) by specific Top1-poisons triggers DNA breaks and cell death. Poly(ADP-ribose) polymerase 1 (PARP1) is an early nick sensor for trapped Top1cc. New mechanistic insights have been developed in recent years to rationalize the importance of PARP1 beyond the repair of Top1-induced DNA breaks. This review summarizes the progress in the molecular mechanisms of trapped Top1cc-induced DNA damage, PARP1 activation at DNA damage sites, PAR-dependent regulation of Top1 nuclear dynamics, and PARP1-associated molecular network for Top1cc repair. Finally, we have discussed the rationale behind the synergy between the combination of Top1 poison and PARP inhibitors in cancer chemotherapies, which is independent of the ‘PARP trapping’ phenomenon.

PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation

“…It has also been suggested that PARylation of TOP1 may play a role for the recruitment of TOP1 to the active sites of rDNA synthesis 33 . To determine whether the stimulation of CPTinduced TOP1-DPCs by PARGi is in part due to dysregulation in TOP1 subnuclear distribution or elevation in TOP1 chromatin localization, we conducted a subcellular fractionation assay in HEK293 cells and found that PARGi did not alter the levels of chromatin-bound TOP1 before and after acute CPT treatment (Supplementary Fig.…”

“…Prompt dePARylation appears to be required for the proteasomal degradation of TOP1-DPCs, as evidence by our observation that PARylated TOP1-DPCs are refractory to degradation by 26S and 20S proteasomes, and that cells treated with PARG inhibitor accumulat and fail to remove TOP1-DPCs. Although PARP1-mediated PARylation recruits TDP1 to TOP1-DPCs 19,33 , it prevents the activity of TDP1 toward TOP1-DPCs in vivo likely because the bulky PAR polymers block the proteolysis hence the exposure of the phosphotyrosyl bond. We, therefore, hypothesize that PARylation of TOP1-DPCs is rapidly reversed by PARG following the co-localization of TDP1 with TOP1-DPCs to enable the proteasomal degradation of the bulky TOP1 adducts.…”

Preventing and Overcoming Resistance to PARP Inhibitors: A Focus on the Clinical Landscape

“…Clinical trials exploring these combinations in unselected populations are already under way and will shed light into the validity of the approach [ 78 , 88 , 89 ]. Given the success of antibody–drug conjugates (ADCs; reviewed in [ 90 ]) harbouring a DNA topoisomerase I (TOP1) inhibitor warhead in breast cancer [ 91 ], and the known synergistic interaction between TOP1 inhibitors and PARPi [ 92 ], combinations of TOP1i-ADCs with PARPi should also be considered. More recently, an SL interaction between BRCAm and loss of the key microhomology-mediated end joining (MMEJ) DNA repair factor DNA polymerase theta (also known as POLQ) has been described [ 93 , 94 ].…”

TDP1 knockout Leishmania donovani accumulate topoisomerase 1‐linked DNA damage and are hypersensitive to clinically used antileishmanial drugs

“…Top1 poisons like CPT stabilize the Top1‐DNA covalent complex (Top1cc) and result in the formation of protein‐linked DNA adducts (PDAs) associated with DNA damage. Unrepaired Top1cc generates DNA double‐strand breaks during its collision with replication and transcription machinery which triggers cell cycle arrest and cell death 2,3,6,12,13 . Accordingly, in the Leishmania parasites, Top1 poisons like CPT accumulate LdTop1 covalent complexes (LdTop1cc) and activate DNA damage and cell death 3,7,13,14 .…”

“…Unrepaired Top1cc generates DNA double-strand breaks during its collision with replication and transcription machinery which triggers cell cycle arrest and cell death. 2,3,6,12,13 Accordingly, in the Leishmania parasites, Top1 poisons like CPT accumulate LdTop1 covalent complexes (LdTop1cc) and activate DNA damage and cell death. 3,7,13,14 Therefore, repair of the trapped Top1cc is an important part of the DNA metabolism and DNA damage response in the parasite.…”