SAMHD1 acts at stalled replication forks to prevent interferon induction

Autoři	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
Rok publikování	2018
Druh	Článek v odborném periodiku
Časopis / Zdroj	Nature
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
Doi	http://dx.doi.org/10.1038/s41586-018-0050-1
Klíčová slova	SAMHD1
Popis	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-Goutieres 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.
Související projekty:	SUMO a stability genomu Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace