Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes

Liton Kumar Saha, Sourav Saha, Xi Yang, Shar-yin Naomi Huang, Yilun Sun, Ukhyun Jo and Yves Pommier ()
Additional contact information
Liton Kumar Saha: NIH
Sourav Saha: NIH
Xi Yang: NIH
Shar-yin Naomi Huang: NIH
Yilun Sun: NIH
Ukhyun Jo: NIH
Yves Pommier: NIH

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Topoisomerase IIIα (TOP3A) belongs to the conserved Type IA family of DNA topoisomerases. Here we report that human TOP3A is associated with DNA replication forks and that a “self-trapping” TOP3A mutant (TOP3A-R364W) generates cellular TOP3A DNA cleavage complexes (TOP3Accs). We show that trapped TOP3Accs that interfere with replication, induce DNA damage and genome instability. To elucidate how TOP3Accs are repaired, we explored the role of Spartan (SPRTN), the metalloprotease associated with DNA replication, which digests proteins forming DNA-protein crosslinks (DPCs). We find that SPRTN-deficient cells show elevated TOP3Accs, whereas overexpression of SPRTN lowers cellular TOP3Accs. SPRTN is deubiquitinated and epistatic with TDP2 in response to TOP3Accs. In addition, we found that MRE11 can excise TOP3Accs, and that cell cycle determines the preference for the SPRTN-TDP2 vs. the ATM-MRE11 pathways, in S vs. G2, respectively. Our study highlights the prevalence of TOP3Accs repair mechanisms to ensure normal DNA replication.

Date: 2023
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DOI: 10.1038/s41467-023-37498-6

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