SAMHD1 acts at stalled replication forks to prevent interferon induction
Authors: Antoine Barthe
Maria-Joao Silva
Alexy Promonet
Bernard Lopez
Karina Zadorozhny
Sushma Sharma
Hervé Técher
Vincenzo Costanzo
Amélie Sarrazin
Monsef Benkirane
Clément Mettling
Elodie Dardillac
Flavie Coquel
Anne-Lyne Schmitz
Andrei Chabes
Jadwiga Nieminuszczy
Wojciech Niedzwiedz
Alexandra Cribier
Yea-Lih Lin
Lumir Krejci
Philippe Pasero
Journal: Nature (2018)
Discipline: Multidisciplinary
Keywords: SAMHD1; dNTPase; viral infections; mutations; cancer development
Affiliations: 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., Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia., IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy., Department of Biology and National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic., Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden., The Institute of Cancer Research, London, UK., Institut de Génétique Humaine, CNRS, Université de Montpellier, Domiciliation, Activation Immunitaire et Infection, Montpellier, France., Université Paris Sud, CNRS, UMR 8200 and Institut de Cancérologie Gustave Roussy, Ligue Contre le Cancer, Villejuif, France., Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire de Virologie Moléculaire, Montpellier, France., BioCampus Montpellier, Université de Montpellier, CNRS, Montpellier, France., International Clinical Research Center, St Anne's University Hospital, Brno, Czech Republic., 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. .

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. 

Retracted: No

PubPeer comments:
 ![file] ![file] What is wrong with the peer review system? , 
 A straightforward supplemental figure with clear results, proper controls and probably very few variability that is also supported by other findings? I don t really see how that would mean the whole peer review was worthless , 
 I think Nature requires a explicit statement of how many times experiments have been performed. I agree that it s always best to perform a replicate experiment to confirm reproducibility, but in this case they aren t trying to quantify the changes in the western blot. Also important to remember that reviewers often ask for additional experiments that have to be completed within the manuscript review deadlines for the journal, so there s not always enough time to do replicates for everything they ask for. I expect that a large proportion of all the western blots in the published literature have only been performed once. Is this ideal? Of course not, but I think the only reason this paper has been flagged is because Nature requires the authors to state how many times they ve performed each experiment. Of course if there s conflicting data out there that suggests this result isn t correct, this would be a great place to post it to start a discussion. I would definitely agree that the inhibition of Chk1 phosphorylation upon Samhd1 immunodepletion is fairly modest, however, if you look in the next figure (Extended data figure 8K) you see that this effect does seem to be reproducible. In fact, Ext Fig8K essentially includes a replicate of the data in Panel 8J. ,