Human Smc5/6 recognises transcription-generated positive DNA supercoils

Aurélie Diman (), Gaël Panis, Cédric Castrogiovanni, Julien Prados, Bastien Baechler and Michel Strubin
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Aurélie Diman: University of Geneva
Gaël Panis: University of Geneva
Cédric Castrogiovanni: University of Geneva
Julien Prados: University of Geneva
Bastien Baechler: University of Geneva
Michel Strubin: University of Geneva

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Beyond its essential roles in ensuring faithful chromosome segregation and genomic stability, the human Smc5/6 complex acts as an antiviral factor. It binds to and impedes the transcription of extrachromosomal DNA templates; an ability which is lost upon integration of the DNA into the chromosome. How the complex distinguishes among different DNA templates is unknown. Here we show that, in human cells, Smc5/6 preferentially binds to circular rather than linear extrachromosomal DNA. We further demonstrate that the transcriptional process, per se, and particularly the accumulation of DNA secondary structures known to be substrates for topoisomerases, is responsible for Smc5/6 recruitment. More specifically, we find that in vivo Smc5/6 binds to positively supercoiled DNA. Those findings, in conjunction with our genome-wide Smc5/6 binding analysis showing that Smc5/6 localizes at few but highly transcribed chromosome loci, not only unveil a previously unforeseen role of Smc5/6 in DNA topology management during transcription but highlight the significance of sensing DNA topology as an antiviral defense mechanism.

Date: 2024
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DOI: 10.1038/s41467-024-50646-w

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