A CHK1-mediated phosphorylation switch suppresses human Topoisomerase 1-associated genomic instability

ABSTRACT: Topoisomerase 1 (TOP1) is essential for relieving DNA supercoils during replication and transcription. However, its transient reaction intermediates (TOP1 cleavage complexes or TOP1-DNA covalent complexes i.e., TOP1ccs) become highly genotoxic when stabilized. While mechanisms that resolve chemotherapy-induced TOP1ccs are well-characterized, how cells prevent their accumulation under physiological conditions for securing genomic stability has remained elusive. Here, we elucidate a novel regulatory pathway in which CHK1-mediated phosphorylation of TOP1 at Serine-320 regulates its re-ligation activity and hence limits steady-state TOP1cc levels during unperturbed cellular metabolism. We further demonstrate a distinct mechanism of TOP1cc stabilization, which escapes recognition by proteasoma

SUBMITTER: Ananda Guha Majumdar 

PROVIDER: S-SCDT-10_1038-S44318-026-00783-3 | biostudies-other |

REPOSITORIES: biostudies-other