CHK1-mediated regulation of TOP1 catalytic activity suppresses replication and transcription-associated genomic instability

Abstract

The Topoisomerase 1 (TOP1) catalytic cycle involves a TOP1-DNA-covalent-complex (TOP1cc), which, if stabilized, can induce rapid accumulation of potentially lethal DNA double strand breaks (DSBs). Although TOP1cc are critically associated with genome instability, it is not yet precisely known how cells regulate TOP1cc level, under unperturbed physiological-condition, to prevent its accumulation and lethal consequences. We discovered a key role of CHK1 in phosphorylating TOP1 at Serine-320 and stimulating TOP1-catalytic cycle to minimise genome wide accumulation of TOP1cc in cancers. Pharmacological or genetic ablation of CHK1-mediated TOP1-phosphorylation leads to stalled replication forks and generates copious amounts of replication/transcription-associated DSBs, R-loops and transcription-replication collisions, eventually leading to chromosomal instability. Further, TOP1ccs stabilized due to CHK1 inhibition are not efficiently targeted by cellular TOP1cc-removal machineries. Since multiple patient clinical trials are ongoing with TOP1- and CHK1-targeting drugs, current finding of CHK1-mediated regulation of TOP1cc may help in better understanding the therapeutic outcomes.