SAMHD1 acts at stalled replication forks to prevent interferon induction
SAMHD1 acts at stalled replication forks to prevent interferon induction
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DOI：
10.1038/s41586-018-0050-1
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发表时间：
2018-05-03
期刊：
影响因子：
64.8
通讯作者：
Pasero, Philippe
中科院分区：
文献类型：
--
作者：
Coquel, Flavie;Silva, Maria-Joao;Pasero, Philippe
SAMHD1以前的特征是保护细胞免受病毒感染的dNTPase。SAMHD1的突变与癌症的发展和一种被称为Aicardi-Goutieres综合征的严重先天性炎症性疾病有关。SAMHD1预防癌症和慢性炎症的机制尚不清楚。在这里，我们表明SAMHD1通过刺激Mre11的核酸外切酶活性，促进了人类细胞系中停滞的复制叉处新生DNA的降解。此功能激活ATR-CHK1检查点，并允许分叉重新启动复制。在SAMHD1缺失的细胞中，单链DNA片段从停滞的叉子中释放并积聚在胞浆中，在那里它们激活cGAS-STING途径，诱导促炎性I型干扰素的表达。因此，SAMHD1是复制应激反应中的一个重要角色，通过限制从停滞的复制叉子释放单链DNA来预防慢性炎症。
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.