Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS.
Sci Adv
; 10(21): eadm8196, 2024 May 24.
Article
en En
| MEDLINE
| ID: mdl-38787953
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
ARN Polimerasa II
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ADN-Topoisomerasas de Tipo I
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Inestabilidad Genómica
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Replicación del ADN
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Roturas del ADN de Doble Cadena
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Estructuras R-Loop
Límite:
Humans
Idioma:
En
Revista:
Sci Adv
Año:
2024
Tipo del documento:
Article
País de afiliación:
Italia