SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks.

  • Major finding: SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks.

  • Concept:SAMHD1 mutations increase cytoplasmic ssDNA, activating the cGAS–STING pathway to induce IFN genes.

  • Impact: SAMHD1 is involved in the replication stress response and thus may suppress tumorigenesis.

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SAMHD1, a dNTPase involved in protecting cells from viral infection, is frequently mutated in solid tumors, chronic lymphocytic leukemia, and the congenital inflammatory disease Aicardi–Goutières syndrome. SAMHD1 loss of function has been suggested to increase spontaneous mutagenesis, genomic instability, and tumorigenesis. However, the mechanism by which SAMHD1 protects against cancer and chronic inflammation has not been fully elucidated. Coquel, Silva, Técher, and colleagues sought to determine the role of SAMHD1 at stalled replication forks. Depleting SAMHD1 resulted in increased cytosolic single-stranded DNA (ssDNA) and induction of IFN genes, especially after exposure to the genotoxic agent hydroxyurea to induce replication fork stalling. These data suggest that SAMHD1 prevents the release of ssDNA from stalled replication forks, preventing activation of the cGAS–STING pathway, which senses cytosolic DNA to trigger type I IFN production. SAMHD1 was observed at replication forks, and SAMHD1 phosphorylation on T592 by CDK was required for normal fork progression. Mechanistically, SAMHD1 bound to replication protein A and fork structures, where it interacted with the exonuclease MRE11, promoting its exonuclease activity and resulting in degradation of nascent DNA at stalled replication forks. This activated the ATR–CHK1 checkpoint to allow forks to restart replication. Thus, mutations in SAMHD1 that affect fork progression are associated with the release of ssDNA into the cytoplasm, which triggers activation of the cGAS–STING pathway and expression of type I IFN. Collectively, these findings reveal a mechanism by which SAMHD1 mutations increase the release of ssDNA from stalled replication forks, promoting accumulation in the cytoplasm to activate the IFN pathway, which may provide insight into their role in tumorigenesis.

Coquel F, Silva MJ, Técher H, Zadorozhny K, Sharma S, Nieminuszczy J, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature 2018;557:57–61.

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