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

Chiara Masnovo, Zohar Paleiov, Daniel Dovrat, Laurel K. Baxter, Sofia Movafaghi, Amir Aharoni and Sergei M. Mirkin ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54977-6

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