SAMHD1 acts at stalled replication forks to prevent interferon induction

Flavie Coquel (1) , Maria-Joao Silva (1, 2) , Hervé Techer (3) , Karina Zadorozhny (4) , Sushma Sharma (5) , Jadwiga Nieminuszczy (6) , Clément Mettling (1) , Elodie Dardillac (7, 8, 9) , Antoine Barthe (1) , Anne-Lyne Schmitz (1) , Alexy Promonet (1) , Alexandra Cribier (1) , Amélie Sarrazin (10, 11) , Wojciech Niedzwiedz (6) , Bernard Lopez (7, 8, 9) , Vincenzo Costanzo (3) , Lumir Krejci (4, 12) , Andrei Chabes (5) , Monsef Benkirane (1) , Yea-Lih Lin (1) , Philippe Pasero (1)

1 IGH - Institut de génétique humaine
2 Peter MacCallum Cancer Centre, East Melbourne, Victoria
3 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
4 MED / MUNI - Department of Biology [Brno]
5 Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå
6 The institute of cancer research [London]
7 UMR 8200 - Stabilité Génétique et Oncogenèse
8 UP11 - Université Paris-Sud - Paris 11
9 Ligue Nationale Contre le Cancer - Paris
10 PHIV MRI - Plateforme RIO Imaging
11 BCM - BioCampus
12 International Clinical Research Center, St Anne's University Hospital, Brno

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.

Domaines: Sciences du Vivant [q-bio]; Génétique

Flavie Coquel, Maria-Joao Silva, Hervé Techer, Karina Zadorozhny, Sushma Sharma, et al.. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature, 2018, 557 (7703), pp.57 - 61. ⟨10.1038/s41586-018-0050-1⟩. ⟨hal-01791237⟩