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

Diana Rubio-Contreras and Fernando Gómez-Herreros ()
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Diana Rubio-Contreras: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla
Fernando Gómez-Herreros: Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla

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

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42622-7

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