SAMHD1 acts at stalled replication forks to prevent interferon induction

Coquel, Flavie; Silva, Maria João; Técher, Hervé; Zadorozhny, Karina; Sharma, Sushma; Nieminuszczy, Jadwiga; Mettling, Clément; Dardillac, Elodie; Barthe, Antoine; Schmitz, Anne-Lyne; Promonet, Alexy; Cribier, Alexandra; Sarrazin, Amélie; Niedźwiedź, Wojciech; Lopez, Bernard S.; Costanzo, Vincenzo; Krejčí, Lumír; Chabes, Andrei; Benkirane, Monsef; Lin, Yea-Lih; Pasero, Philippe

doi:10.1038/s41586-018-0050-1

Cited by 362 publications

(433 citation statements)

References 59 publications

Supporting

Mentioning

404

Contrasting

Order By: Relevance

“…We previously showed that SAMHD1 expression in normal human fibroblasts changes with their proliferation state. 11 The latter function of SAMHD1 permits the degradation of ssDNA stretches removed from the stalled forks preventing accumulation of ssDNA in the cytosol and induction of the interferon response. 8 During S phase CDK-cyclin complexes phosphorylate SAMHD1 at T592 with still debated functional implications.…”

Section: Introductionmentioning

confidence: 99%

“…8 The protein accumulates in G0/G1 and quiescent cell states, which suggested that the enzyme may exert its activity mainly outside S phase. 11 Genetic defects in SAMHD1 cause human pathologies linked to either of the two recognized functions of the protein, that is, as a dNTP pool regulator and a defense against inflammatory response. At first, T592 phosphorylation was interpreted as a mechanism to inactivate or downregulate SAMHD1 triphosphohydrolase activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

et al. 2019

View full text Add to dashboard Cite

In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and concentration of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Imbalanced dNTP pools increase mutation frequency in cancer cells, but it is not known if the SAMHD1induced dNTP imbalance favors accumulation of somatic mutations in nontransformed cells. Here, we have investigated how fibroblasts from Aicardi-Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell cycle progression, dynamics and fidelity of DNA replication, and efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages. To investigate whether the lack of SAMHD1 affects DNA replication fidelity, we compared de novo mutations in AGS and WT cells by exome next-generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic, promoting genome instability in nontransformed cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

et al. 2019

View full text Add to dashboard Cite

show abstract

“…AGS patients with SAMHD1 mutations do not display an accumulation of rNMPs (Lim et al, 2015), but the activation of an IFN response is similarly evoked by cGAS-STING-mediated sensing of endogenous DNA species in the cytoplasm (Coquel et al, 2018). AGS patients with SAMHD1 mutations do not display an accumulation of rNMPs (Lim et al, 2015), but the activation of an IFN response is similarly evoked by cGAS-STING-mediated sensing of endogenous DNA species in the cytoplasm (Coquel et al, 2018).…”

Section: Compromised Rer Causes Aicardi-goutières Syndromementioning

confidence: 99%

Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

Kellner

Luke

2019

The EMBO Journal

View full text Add to dashboard Cite

The duplication of the eukaryotic genome is an intricate process that has to be tightly safe-guarded. One of the most frequently occurring errors during DNA synthesis is the mis-insertion of a ribonucleotide instead of a deoxyribonucleotide. Ribonucleotide excision repair (RER) is initiated by RNase H2 and results in errorfree removal of such mis-incorporated ribonucleotides. If left unrepaired, DNA-embedded ribonucleotides result in a variety of alterations within chromosomal DNA, which ultimately lead to genome instability. Here, we review how genomic ribonucleotides lead to chromosomal aberrations and discuss how the tight regulation of RER timing may be important for preventing unwanted DNA damage. We describe the structural impact of unrepaired ribonucleotides on DNA and chromatin and comment on the potential consequences for cellular fitness. In the context of the molecular mechanisms associated with faulty RER, we have placed an emphasis on how and why increased levels of genomic ribonucleotides are associated with severe autoimmune syndromes, neuropathology, and cancer. In addition, we discuss therapeutic directions that could be followed for pathologies associated with defective removal of ribonucleotides from doublestranded DNA.

show abstract

“…A recent study using SAMHD1-deficent mice showed these mice lack autoimmune phenotypes but are hyperactive in cGAS/STING signaling and induce the expression of type I IFN genes Ifit1 and Ifi44 (Behrendt et al, 2013; Maelfait et al, 2016). Additionally, SAMHD1 has also been implicated in DNA damage responses through its ability to maintain genome stability, digest ssDNA fragments at stalling replication forks, and inhibiting a cGAS/STING inflammatory response (Coquel et al, 2018; Kretschmer et al, 2015; Medeiros et al, 2018). A recent study has shown that SAMHD1 can suppress innate immune induction independently of its dNTPase activity.…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

View full text Add to dashboard Cite

Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

show abstract

SAMHD1 acts at stalled replication forks to prevent interferon induction

Cited by 362 publications

References 59 publications

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Contact Info

Product

Resources

About