TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription

DNA topoisomerase I (TOP1) removes torsional stress by transiently cutting one DNA strand. Such cuts are rejoined by TOP1 but can occasionally become abortive generating permanent protein-linked single strand breaks (SSBs). The repair of these breaks is initiated by tyrosyl-DNA phosphodiesterase 1 (...

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Published in:Nature communications 2023-11, Vol.14 (1), p.6940-6940, Article 6940
Main Authors: Rubio-Contreras, Diana, Gómez-Herreros, Fernando
Format: Article
Language:English
Subjects:
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Cell death
Chromosome translocations
Deoxyribonucleic acid
DNA
DNA damage
DNA topoisomerase
Genomes
Humanities and Social Sciences
multidisciplinary
Non-homologous end joining
Phosphodiesterase
Science
Science (multidisciplinary)
Torsional stress
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Summary:DNA topoisomerase I (TOP1) removes torsional stress by transiently cutting one DNA strand. Such cuts are rejoined by TOP1 but can occasionally become abortive generating permanent protein-linked single strand breaks (SSBs). The repair of these breaks is initiated by tyrosyl-DNA phosphodiesterase 1 (TDP1), a conserved enzyme that unlinks the TOP1 peptide from the DNA break. Additionally, some of these SSBs can result in double strand breaks (DSBs) either during replication or by a poorly understood transcription-associated process. In this study, we identify these DSBs as a source of genome rearrangements, which are suppressed by TDP1. Intriguingly, we also provide a mechanistic explanation for the formation of chromosomal translocations unveiling an error-prone pathway that relies on the MRN complex and canonical non-homologous end-joining. Collectively, these data highlight the threat posed by TOP1-induced DSBs during transcription and demonstrate the importance of TDP1-dependent end-joining in protecting both gene transcription and genome stability. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs single strand breaks (SSBs) generated by DNA topoisomerase I (TOP1). Here the authors show that TDP1 also repairs TOP1-induced double strand breaks (DSBs).
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-42622-7