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A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome

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journal contribution
posted on 2023-06-09, 19:59 authored by William GittensWilliam Gittens, Dominic J Johnson, Rachal M Allison, Timothy Cooper, Holly Thomas, Matt NealeMatt Neale
DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo.

Funding

Control and impact of meiotic DNA resection on recombination and genome stability; G1538; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/M010279/1

Biochemical reconstitution of DNA repair reactions on intact chromatin; G0986; EUROPEAN UNION; 311336

Spatial regulation of meiotic recombination; G2004; WELLCOME TRUST; 200843/Z/16/Z

History

Publication status

  • Published

File Version

  • Published version

Journal

Nature Communications

ISSN

2041-1723

Publisher

Nature Research

Volume

10

Article number

a4846

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2020-01-07

First Open Access (FOA) Date

2020-01-07

First Compliant Deposit (FCD) Date

2020-01-06

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