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<p>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>i.e.,</i> 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 religation 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 proteasomal and autophagic machineries, while being susceptible to CtIP, SPRTN, and p97-mediated removal. Defective phosphorylation of TOP1 at S320 impairs replication-fork progression, leading to replication- and transcription-associated DSBs, R-loop stabilization, genomic instability, and hypersensitivity to TOP1 poisons. Overall, our study assigns a new function to CHK1&#xa0;in direct regulation of human TOP1cc dynamics, with critical implications for genomic integrity and combinatorial chemotherapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Ananda Guha Majumdar,
  • Nitish Chauhan,
  • Pooja Gupta,
  • Mahesh Subramanian,
  • Birija Sankar Patro

摘要

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 religation 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 proteasomal and autophagic machineries, while being susceptible to CtIP, SPRTN, and p97-mediated removal. Defective phosphorylation of TOP1 at S320 impairs replication-fork progression, leading to replication- and transcription-associated DSBs, R-loop stabilization, genomic instability, and hypersensitivity to TOP1 poisons. Overall, our study assigns a new function to CHK1 in direct regulation of human TOP1cc dynamics, with critical implications for genomic integrity and combinatorial chemotherapy.