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SAMHD1 acts at stalled replication forks to prevent interferon induction
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2018 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 557, no 7703, p. 57-61Article in journal (Refereed) Published
Abstract [en]

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS-STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

Place, publisher, year, edition, pages
2018. Vol. 557, no 7703, p. 57-61
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Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-147779DOI: 10.1038/s41586-018-0050-1ISI: 000431234500029PubMedID: 29670289OAI: oai:DiVA.org:umu-147779DiVA, id: diva2:1206720
Available from: 2018-05-17 Created: 2018-05-17 Last updated: 2018-06-09Bibliographically approved

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Sharma, SushmaChabes, Andrei

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Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)
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