Cohesin causes replicative DNA damage by trapping DNA topological stress

Minchell, Nicola Elizabeth, Keszthelyi, Andrea and Baxter, Jonathan (2020) Cohesin causes replicative DNA damage by trapping DNA topological stress. Molecular cell, 78. pp. 1-13. ISSN 1097-2765

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Abstract

DNA topological stress inhibits DNA replication fork (RF) progression and contributes to DNA replication stress. In Saccharomyces cerevisiae, we demonstrate that centromeric DNA and the rDNA array are especially vulnerable to DNA topological stress during replication. The activity of the SMC complexes cohesin and condensin are linked to both the generation and repair of DNA topological-stress-linked damage in these regions. At cohesin-enriched centromeres, cohesin activity causes the accumulation of DNA damage, RF rotation, and pre-catenation, confirming that cohesin-dependent DNA topological stress impacts on normal replication progression. In contrast, at the rDNA, cohesin and condensin activity inhibit the repair of damage caused by DNA topological stress. We propose that, as well as generally acting to ensure faithful genetic inheritance, SMCs can disrupt genome stability by trapping DNA topological stress.

Item Type: Article
Keywords: DNA replication, DNA topology, DNA topoisomerase, cohesin condensin, DNA damage
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0460 Mutations
Q Science > QP Physiology > QP0501 Animal biochemistry > QP0550 Organic substances > QP0551 Proteins, amino acids, etc. > QP0601 Enzymes > QP0615 Isomerases > QP0616.A-Z Special, A-Z > QP0616.D56 DNA topoisomerases
Depositing User: Jon Baxter
Date Deposited: 15 Apr 2020 07:27
Last Modified: 15 Apr 2020 07:30
URI: http://sro.sussex.ac.uk/id/eprint/90742

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Project NameSussex Project NumberFunderFunder Ref
Investigating how replication fork rotation causes chromosomal instability during S phaseG1903BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/N007344/1