Distinct roles for S. cerevisiae H2A copies in recombination and repeat stability, with a role for H2A.1 threonine 126

Abstract

CAG/CTG trinuncleotide repeats are fragile sequences that when expanded form DNA secondary structures and cause human disease. We evaluated CAG/CTG repeat stability and repair outcomes in histone H2 mutants in S. cerevisiae. Although the two copies of H2A are nearly identical in amino acid sequence, CAG repeat stability depends on H2A copy 1 (H2A.1) but not copy 2 (H2A.2). H2A.1 promotes high-fidelity homologous recombination, sister chromatid recombination (SCR), and break-induced replication whereas H2A.2 does not share these functions. Both decreased SCR and the increase in CAG expansions were due to the unique Thr126 residue in H2A.1 and hta1Δ or hta1-T126A mutants were epistatic to deletion of the Polδ subunit Pol32, suggesting a role for H2A.1 in D-loop extension. We conclude that H2A.1 plays a greater repair-specific role compared to H2A.2 and may be a first step towards evolution of a repair-specific function for H2AX compared to H2A in mammalian cells.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Nealia CM House

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  2. Erica J Polleys

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  3. Ishtiaque Quasem

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  4. Marjorie De la Rosa Mejia

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  5. Cailin E Joyce

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    Cailin E Joyce, is affiliated with Agenus Inc. The author has no financial interests to declare.
  6. Oliver Takacsi-Nagy

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    Oliver Takacsi-Nagy, is affiliated with ArsenalBio. The author has no financial interests to declare.
  7. Jocelyn E Krebs

    Department of Biological Sciences, University of Alaska, Anchorage, Anchorage, United States
    Competing interests
    No competing interests declared.
  8. Stephen M Fuchs

    Department of Biology, Tufts University, Medford, United States
    Competing interests
    No competing interests declared.
  9. Catherine H Freudenreich

    Department of Biology, Tufts University, Medford, United States
    For correspondence
    catherine.freudenreich@tufts.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1652-2917

Funding

National Institutes of Health (P01GM105473)

  • Catherine H Freudenreich

American Cancer Society (PF-18-125-10-DMC)

  • Erica J Polleys

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wolf-Dietrich Heyer, University of California, Davis, United States

Publication history

  1. Received: November 6, 2019
  2. Accepted: November 26, 2019
  3. Accepted Manuscript published: December 5, 2019 (version 1)
  4. Version of Record published: December 23, 2019 (version 2)

Copyright

© 2019, House et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nealia CM House
  2. Erica J Polleys
  3. Ishtiaque Quasem
  4. Marjorie De la Rosa Mejia
  5. Cailin E Joyce
  6. Oliver Takacsi-Nagy
  7. Jocelyn E Krebs
  8. Stephen M Fuchs
  9. Catherine H Freudenreich
(2019)
Distinct roles for S. cerevisiae H2A copies in recombination and repeat stability, with a role for H2A.1 threonine 126
eLife 8:e53362.
https://doi.org/10.7554/eLife.53362
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