DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I–DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA- RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc- triggered hybrids and DNA double- strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms. DSBs are at highly transcribed genes in early replicating initiation zones and overlap with hybrids downstream of accumulated RNA polymerase II (RNAPII) at gene 5′- ends. A transcription factor IIS mutant impairing transcription elongation further increased RNAPII accumulation likely due to backtracking. Moreover, Top1ccs can trigger micronuclei when occurring during late G1 or early/mid S, but not during late S. As micronuclei and transcription- replication conflicts are attenuated by transcription factor IIS, our results support a role of RNAPII arrest in Top1cc- induced transcription- replication conflicts leading to DSBs and micronuclei.

Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS / Renée Concetta Duardo , Jessica Marinello , Marco Russo , Sara Morelli , Simona Pepe , Federico Guerra , Belén Gómez-González , Andrés Aguilera , Giovanni Capranico. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - ELETTRONICO. - 10:(2024), pp. 1-21.

Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS

Renée Concetta Duardo;Jessica Marinello;Marco Russo;Sara Morelli;Simona Pepe;Federico Guerra;Giovanni Capranico
2024

Abstract

DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I–DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA- RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc- triggered hybrids and DNA double- strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms. DSBs are at highly transcribed genes in early replicating initiation zones and overlap with hybrids downstream of accumulated RNA polymerase II (RNAPII) at gene 5′- ends. A transcription factor IIS mutant impairing transcription elongation further increased RNAPII accumulation likely due to backtracking. Moreover, Top1ccs can trigger micronuclei when occurring during late G1 or early/mid S, but not during late S. As micronuclei and transcription- replication conflicts are attenuated by transcription factor IIS, our results support a role of RNAPII arrest in Top1cc- induced transcription- replication conflicts leading to DSBs and micronuclei.
2024
Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS / Renée Concetta Duardo , Jessica Marinello , Marco Russo , Sara Morelli , Simona Pepe , Federico Guerra , Belén Gómez-González , Andrés Aguilera , Giovanni Capranico. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - ELETTRONICO. - 10:(2024), pp. 1-21.
Renée Concetta Duardo , Jessica Marinello , Marco Russo , Sara Morelli , Simona Pepe , Federico Guerra , Belén Gómez-González , Andrés Aguilera , Giov...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/970605
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