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Mutation in histone deacetylase clr6 promotes the survival of S. pombe cds1 null mutant in response to hydroxyurea

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Abstract

Fission yeast Cds1 is responsible for the replication checkpoint activation and helps to protect replication fork collapse in response to hydroxyurea (HU). Here, we investigated the role of histone deacetylase in response to replication fork arrest and observed that in the presence of HU, the survival of cds1Δ cells was improved when the cells were simultaneously treated with histone deacetylase inhibitors. Furthermore, a mutation in the histone deacetylase gene, clr6, also suppresses the growth defect of cds1Δ cells in response to HU indicating a suppressive role of clr6-1 mutation in cds1 deletion background upon HU treatment. Interestingly, in response to HU, phosphorylation of Chk1 kinase and the number of Rad52YFP foci was reduced in cds1Δ clr6-1 double mutant as compared to cds1Δ single mutant indicating a decrease in the level of DNA damage in response to HU. Accordingly, the single-cell gel electrophoresis assay revealed a drastic reduction in the tail length of cds1Δ clr6-1 double mutant as compared to cds1Δ cells in the presence of HU suggesting the suppression of chromosomal defects in the double mutant. Taken together, we proposed that there could be transient suppression of fork collapse in cds1Δ clr6-1 double mutant upon HU treatment due to the delay in mitotic progression that leads to the facilitation of cell growth.

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Acknowledgements

We thank the members of our lab for helpful discussions and technical support, and Dr. Niti Kumar and Dr. JV Pratap for critical reading of the manuscript and useful suggestions. We thank Dr. Lorraine Pillus and Dr. Jagmohan Singh for the sir2 and clr3 knockout strains. This work was supported by the grants from the Council of Scientific and Industrial Research and Department of Science and Technology, New Delhi, India. SK and NA acknowledge Indian Council of Medical Research (ICMR), and LP acknowledge the University Grant Commission (UGC) for providing research fellowship. The Funding was provided by Science and Engineering Research Board (GAP0217). The CDRI communication number for this manuscript is 10044.

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  1. Saman Khan & Nafees Ahamad

    Present address: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA

Authors and Affiliations

  1. Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Lalita Panigrahi & Shakil Ahmed

  2. Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854-5635, USA

    Nancy Walworth

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  1. Saman Khan
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Correspondence to Shakil Ahmed.

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Khan, S., Ahamad, N., Panigrahi, L. et al. Mutation in histone deacetylase clr6 promotes the survival of S. pombe cds1 null mutant in response to hydroxyurea. Mol Genet Genomics 295, 695–703 (2020). https://doi.org/10.1007/s00438-020-01655-z

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