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Chemical Dimerization-Induced Protein Condensates on Telomeres
Published on: April 12, 2021
A Critical Role for Dna2 at Unwound Telomeres
Marta Markiewicz-Potoczny1, Michael Lisby2, David Lydall3
1Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
Abstract:
Dna2 is a nuclease and helicase that functions redundantly with other proteins in Okazaki fragment processing, double-strand break resection, and checkpoint kinase activation. Dna2 is an essential enzyme, required for yeast and mammalian cell viability. Here, we report that numerous mutations affecting the DNA damage checkpoint suppress dna2∆ lethality in Saccharomyces cerevisiaedna2∆ cells are also suppressed by deletion of helicases PIF1 and MPH1, and by deletion of POL32, a subunit of DNA polymerase δ. All dna2∆ cells are temperature sensitive, have telomere length defects, and low levels of telomeric 3' single-stranded DNA (ssDNA). Interestingly, Rfa1, a subunit of the major ssDNA binding protein RPA, and the telomere-specific ssDNA binding protein Cdc13, often colocalize in dna2∆ cells. This suggests that telomeric defects often occur in dna2∆ cells. There are several plausible explanations for why the most critical function of Dna2 is at telomeres. Telomeres modulate the DNA damage response at chromosome ends, inhibiting resection, ligation, and cell-cycle arrest. We suggest that Dna2 nuclease activity contributes to modulating the DNA damage response at telomeres by removing telomeric C-rich ssDNA and thus preventing checkpoint activation.
Insights
DNA2 is essential for cell viability, acting as a nuclease and helicase. Its absence causes telomere defects, but mutations in DNA damage checkpoint genes can suppress this lethality.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Dna2 is a crucial enzyme with nuclease and helicase functions, essential for DNA replication and repair processes like Okazaki fragment processing and double-strand break resection.
- Dna2 plays a vital role in checkpoint kinase activation and is indispensable for the viability of yeast and mammalian cells.
Purpose of the Study:
- To investigate the lethality suppression of dna2 deletion mutants in Saccharomyces cerevisiae.
- To explore the role of Dna2 in telomere maintenance and its connection to the DNA damage response.
Main Methods:
- Genetic screening for mutations that suppress dna2∆ lethality.
- Analysis of telomere length and telomeric single-stranded DNA (ssDNA) in dna2∆ cells.
- Investigating the colocalization of ssDNA binding proteins (Rfa1, Cdc13) in dna2∆ cells.
Main Results:
- Mutations in DNA damage checkpoint genes, as well as deletions of helicases PIF1 and MPH1, and POL32, suppress dna2∆ lethality.
- dna2∆ cells exhibit temperature sensitivity, telomere length defects, and reduced telomeric 3' ssDNA.
- Colocalization of RPA subunit Rfa1 and telomere-specific protein Cdc13 in dna2∆ cells indicates telomeric defects.
Conclusions:
- Dna2's essential function is linked to telomere maintenance and modulation of the DNA damage response at chromosome ends.
- Dna2's nuclease activity likely removes telomeric C-rich ssDNA, preventing aberrant checkpoint activation.
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