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Nature. 2018 May;557(7703):57-61. doi: 10.1038/s41586-018-0050-1. Epub 2018 Apr 18.

SAMHD1 acts at stalled replication forks to prevent interferon induction.

Author information

1
Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l'Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer, Montpellier, France.
2
Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
3
IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy.
4
Department of Biology and National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic.
5
Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
6
The Institute of Cancer Research, London, UK.
7
Institut de Génétique Humaine, CNRS, Université de Montpellier, Domiciliation, Activation Immunitaire et Infection, Montpellier, France.
8
Université Paris Sud, CNRS, UMR 8200 and Institut de Cancérologie Gustave Roussy, Ligue Contre le Cancer, Villejuif, France.
9
Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire de Virologie Moléculaire, Montpellier, France.
10
BioCampus Montpellier, Université de Montpellier, CNRS, Montpellier, France.
11
International Clinical Research Center, St Anne's University Hospital, Brno, Czech Republic.
12
Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l'Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer, Montpellier, France. ylin@igh.cnrs.fr.
13
Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l'Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer, Montpellier, France. ppasero@igh.cnrs.fr.

Abstract

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.

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PMID:
29670289
DOI:
10.1038/s41586-018-0050-1
[Indexed for MEDLINE]

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