Journal
NATURE
Volume 557, Issue 7703, Pages 57-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-018-0050-1
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Funding
- Agence Nationale pour la Recherche (ANR)
- Institut National du Cancer (INCa)
- Ligue Contre le Cancer (equipe labellisee)
- Canceropole Grand Sud-ouest
- SIRIC Montpellier Cancer
- MSDAvenir fund
- Medical Research Council
- Institute of Cancer Research
- Swedish Cancer Society
- Swedish Research Council
- Czech Science Foundation [GACR 17-17720S, 13-26629S]
- National Program of Sustainability II (MEYS CR) [LQ1605]
- CNRS, Region LR
- Fondation ARC
- French MRES
- Fondation Recherche Medicale
- Associazione Italiana per Ricerca sul Cancro (AIRC)
- European Research Council (ERC) Consolidator Grant [614541]
- Armenise-Harvard Foundation career development award
- AICR Worldwide Cancer Research award [13-0026]
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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.
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