IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54977-6.html
   My bibliography  Save this article

Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability

Author

Listed:
  • Chiara Masnovo

    (Tufts University)

  • Zohar Paleiov

    (Ben-Gurion University of the Negev)

  • Daniel Dovrat

    (Ben-Gurion University of the Negev)

  • Laurel K. Baxter

    (Tufts University)

  • Sofia Movafaghi

    (Tufts University)

  • Amir Aharoni

    (Ben-Gurion University of the Negev)

  • Sergei M. Mirkin

    (Tufts University)

Abstract

Trinucleotide repeats, including Friedreich’s ataxia (GAA)n repeats, become pathogenic upon expansions during DNA replication and repair. Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. Supporting this conclusion, live-cell microscopy experiments reveal increased replication fork stalling at the repeat in mcm10-1 cells. Unexpectedly, the viability of strains containing a single (GAA)100 repeat at an essential chromosomal location strongly depends on Mcm10 function and cellular RPA levels. This coincides with Rad9 checkpoint activation, which promotes cell viability, but initiates repeat expansions via DNA synthesis by polymerase δ. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.

Suggested Citation

  • Chiara Masnovo & Zohar Paleiov & Daniel Dovrat & Laurel K. Baxter & Sofia Movafaghi & Amir Aharoni & Sergei M. Mirkin, 2024. "Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54977-6
    DOI: 10.1038/s41467-024-54977-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54977-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54977-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ryan M. Baxley & Wendy Leung & Megan M. Schmit & Jacob Peter Matson & Lulu Yin & Marissa K. Oram & Liangjun Wang & John Taylor & Jack Hedberg & Colette B. Rogers & Adam J. Harvey & Debashree Basu & Je, 2021. "Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    2. Aline C. Simon & Jin C. Zhou & Rajika L. Perera & Frederick van Deursen & Cecile Evrin & Marina E. Ivanova & Mairi L. Kilkenny & Ludovic Renault & Svend Kjaer & Dijana Matak-Vinković & Karim Labib & A, 2014. "A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome," Nature, Nature, vol. 510(7504), pages 293-297, June.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54977-6. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.