SAD-6/ATRX enables broad genome surveillance and defense in fungi

Carlier, F.; Klimova, A.; Bouscasse, E.; Wang, Z.; Loiodice, I.; Taddei, A.; Kronholm, I.; Dunlap, J. C.; Matondo, M.; Gladyshev, E.

doi:10.64898/2026.08.11.744009

bioRxiv · 10.64898/2026.08.11.744009

SAD-6/ATRX enables broad genome surveillance and defense in fungi

Carlier, F.·Klimova, A.·Bouscasse, E.·Wang, Z.·Loiodice, I.·Taddei, A.·Kronholm, I.·Dunlap, J. C.·Matondo, M.·Gladyshev, E.

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Abstract

The chromatin remodeler ATRX and its orthologs maintain genome function by regulating repetitive DNA and dynamic chromatin, and their activities have been canonically associated with replication-independent deposition of the histone H3.3 variant. This model is difficult to reconcile with fungi, which encode ATRX orthologs but lack H3 variants that may separately support replication-coupled and replication-independent deposition. Here we show that the fungal ATRX ortholog SAD-6 instead relies on a highly divergent histone H4 variant (H4v) to mediate broad genome surveillance and defense. Deposition of H4v is strictly SAD-6-dependent and thus provides a sensitive genome-wide readout of SAD-6 activity, revealing its functions at telomeres, tRNA and rDNA loci, AT-rich DNA, artificial transgenes, decaying mobile elements, and many genic regions. We further show that SAD-6 is required for a pathway of repeat-induced point mutation (RIP) that also requires DIM-5, a conserved SUV39 methyltransferase that mediates trimethylation of histone H3 lysine-9 in heterochromatin. Together, these findings establish ATRX-like remodelers as broad regulators of genome surveillance and defense in fungi that act through a highly divergent histone H4 variant rather than H3.3. Given that RIP is proposed to recognize repetitive DNA via recombination-independent homologous pairing, the requirement for SAD-6 in RIP suggests that ATRX-like remodelers may couple DNA pairing to heterochromatin nucleation on repeats.

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Carlier, F., Klimova, A., Bouscasse, E., Wang, Z., Loiodice, I., Taddei, A., Kronholm, I., Dunlap, J. C., Matondo, M., Gladyshev, E.. 2026-08-11. SAD-6/ATRX enables broad genome surveillance and defense in fungi. https://doi.org/10.64898/2026.08.11.744009

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