SAMHD1 acts at stalled replication forks to prevent interferon induction
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29670289
DOI
10.1038/s41586-018-0050-1
PII: 10.1038/s41586-018-0050-1
Knihovny.cz E-resources
- MeSH
- Checkpoint Kinase 1 metabolism MeSH
- Cytosol metabolism MeSH
- HEK293 Cells MeSH
- HeLa Cells MeSH
- RecQ Helicases metabolism MeSH
- MRE11 Homologue Protein metabolism MeSH
- Interferon Type I immunology metabolism MeSH
- DNA, Single-Stranded metabolism MeSH
- Humans MeSH
- Membrane Proteins metabolism MeSH
- Nucleotidyltransferases metabolism MeSH
- SAM Domain and HD Domain-Containing Protein 1 deficiency metabolism MeSH
- DNA Replication * MeSH
- Inflammation immunology metabolism prevention & control MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- cGAS protein, human MeSH Browser
- Checkpoint Kinase 1 MeSH
- CHEK1 protein, human MeSH Browser
- RecQ Helicases MeSH
- MRE11 Homologue Protein MeSH
- Interferon Type I MeSH
- DNA, Single-Stranded MeSH
- Membrane Proteins MeSH
- MRE11 protein, human MeSH Browser
- Nucleotidyltransferases MeSH
- SAM Domain and HD Domain-Containing Protein 1 MeSH
- RECQL protein, human MeSH Browser
- SAMHD1 protein, human MeSH Browser
- STING1 protein, human MeSH Browser
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.
BioCampus Montpellier Université de Montpellier CNRS Montpellier France
IFOM The FIRC Institute of Molecular Oncology Milan Italy
International Clinical Research Center St Anne's University Hospital Brno Czech Republic
Peter MacCallum Cancer Centre East Melbourne Victoria Australia
References provided by Crossref.org
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