Format

Send to

Choose Destination
Nucleic Acids Res. 2019 Jul 27. pii: gkz631. doi: 10.1093/nar/gkz631. [Epub ahead of print]

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability.

Author information

1
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
2
Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY 10032, USA.
3
Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Abstract

The postreplication repair gene, HLTF, is often amplified and overexpressed in cancer. Here we model HLTF dysregulation through the functionally conserved Saccharomyces cerevisiae ortholog, RAD5. Genetic interaction profiling and landscape enrichment analysis of RAD5 overexpression (RAD5OE) reveals requirements for genes involved in recombination, crossover resolution, and DNA replication. While RAD5OE and rad5Δ both cause cisplatin sensitivity and share many genetic interactions, RAD5OE specifically requires crossover resolving genes and drives recombination in a region of repetitive DNA. Remarkably, RAD5OE induced recombination does not require other post-replication repair pathway members, or the PCNA modification sites involved in regulation of this pathway. Instead, the RAD5OE phenotype depends on a conserved domain necessary for binding 3' DNA ends. Analysis of DNA replication intermediates supports a model in which dysregulated Rad5 causes aberrant template switching at replication forks. The direct effect of Rad5 on replication forks in vivo, increased recombination, and cisplatin sensitivity predicts similar consequences for dysregulated HLTF in cancer.

PMID:
31350889
DOI:
10.1093/nar/gkz631

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center