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@article{1729970,
author = {Coquel, Flavie and Silva, MariaandJoao and Techer, Hervé and Zadorozhny, Karina and Sharma, Sushma and Nieminuszczy, Jadwiga and Mettling, Clément and Dardillac, Elodie and Barthe, Antoine and Schmitz, AnneandLyne and Promonet, Alexy and Cribier, Alexandra and Sarrazin, Amélie and Niedzwiedz, Wojciech and Lopez, Bernard and Costanzo, Vincenzo and Krejčí, Lumír and Chabes, Andrei and Benkirane, Monsef and YeaandLih, Lin and Pasero, Philippe},
article_number = {1},
doi = {http://dx.doi.org/10.5802/crbiol.10},
keywords = {Chronic inflammation; Stalled forks},
language = {eng},
issn = {1631-0691},
journal = {Comptes Rendus - Biologies},
title = {SAMHD1 acts at stalled replication forks to prevent interferon induction},
url = {https://doi.org/10.1038/s41586-018-0050-1},
volume = {343},
year = {2020}
}
TY - JOUR
ID - 1729970
AU - Coquel, Flavie - Silva, Maria-Joao - Techer, Hervé - Zadorozhny, Karina - Sharma, Sushma - Nieminuszczy, Jadwiga - Mettling, Clément - Dardillac, Elodie - Barthe, Antoine - Schmitz, Anne-Lyne - Promonet, Alexy - Cribier, Alexandra - Sarrazin, Amélie - Niedzwiedz, Wojciech - Lopez, Bernard - Costanzo, Vincenzo - Krejčí, Lumír - Chabes, Andrei - Benkirane, Monsef - Yea-Lih, Lin - Pasero, Philippe
PY - 2020
TI - SAMHD1 acts at stalled replication forks to prevent interferon induction
JF - Comptes Rendus - Biologies
VL - 343
IS - 1
SP - 9-21
EP - 9-21
PB - Académie des sciences
SN - 16310691
KW - Chronic inflammation
KW - Stalled forks
UR - https://doi.org/10.1038/s41586-018-0050-1
L2 - https://doi.org/10.1038/s41586-018-0050-1
N2 - DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutieres syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutieres syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutieres syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.
ER -
COQUEL, Flavie, Maria-Joao SILVA, Hervé TECHER, Karina ZADOROZHNY, Sushma SHARMA, Jadwiga NIEMINUSZCZY, Clément METTLING, Elodie DARDILLAC, Antoine BARTHE, Anne-Lyne SCHMITZ, Alexy PROMONET, Alexandra CRIBIER, Amélie SARRAZIN, Wojciech NIEDZWIEDZ, Bernard LOPEZ, Vincenzo COSTANZO, Lumír KREJČÍ, Andrei CHABES, Monsef BENKIRANE, Lin YEA-LIH and Philippe PASERO. SAMHD1 acts at stalled replication forks to prevent interferon induction. \textit{Comptes Rendus - Biologies}. Académie des sciences, 2020, vol.~343, No~1, p.~9-21. ISSN~1631-0691. Available from: https://dx.doi.org/10.5802/crbiol.10.
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