Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response

Malone, Dane; Lardelli, Rea M.; Li, Manqing; David, Michael

doi:10.1074/jbc.ra118.006588

Cited by 34 publications

(34 citation statements)

References 18 publications

(46 reference statements)

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“…These molecular effects of SLFN11 have been linked to its putative helicase activity encoded in the C-terminal domain of SLFN11 ( Figure 6 B) [ 85 , 118 , 129 , 131 ]. In addition, SLFN11 has been found to act outside of the nucleus by degrading type II tRNAs and blocking the translation of ATR and ATM [ 133 , 134 , 135 ]. This ribonuclease function of SLFN11 is likely related to its N-terminal domain, which is conserved in all of human SLFN genes ( Figure 6 B) [ 133 , 136 ].…”

Section: Exploiting Slfn11 As a Therapeutic Biomarkermentioning

confidence: 99%

“…Indeed, SLFN11 is normally expressed in lymphocytes [ 11 , 126 ]. Moreover, SLFN11 activity is not limited to the nucleus [ 133 , 134 , 135 , 137 , 147 ] and it remains to be determined whether cytosolic IHC staining of SLFN11 should be taken into consideration [ 141 , 148 ]. This is particularly relevant to the fact that human SLFN proteins including SLFN5, 11, 12, 12L, 13, and 14 have strong similarity in their amino acid sequence ( Figure 6 B) [ 11 , 149 ] and that some of these SLFN proteins only act in the cytosol [ 149 , 150 ].…”

Section: Exploiting Slfn11 As a Therapeutic Biomarkermentioning

confidence: 99%

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Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Murai

Takebe

et al. 2021

Cancers

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Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.

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Section: Exploiting Slfn11 As a Therapeutic Biomarkermentioning

confidence: 99%

Section: Exploiting Slfn11 As a Therapeutic Biomarkermentioning

confidence: 99%

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Murai

Takebe

et al. 2021

Cancers

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“…HIST1H2BJ is identified for predicting the prognosis of cervical cancer patients 26 . PPP1CC is required for SLFN11 to cleave tRNAs and further to inhibit the translation 27 . G protein, GPCR, and related proteins are involved in widely physiological and pathophysiological processes 28-33 .…”

Section: Discussionmentioning

confidence: 99%

Identification of biomarkers and pathways of mouse embryonic fibroblasts with the dysfunction of mitochondrial DNA

2021

Preprint

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Mitochondrial diseases are clinically heterogeneous which involve multiple systems such as organs that are highly dependent on metabolism. Dysfunction of mtDNA is the main cause of mitochondrial diseases that trigger inflammation and immune responses. Here, we aim to identify the biological function and pathways of MEFs with the dysfunction of mtDNA through deletion of YME1L. The gene expression profiles of GSE161735 dataset were originally created by the Illumina NovaSeq 6000 (Mus musculus) for gene biogenesis and function panel. The biological and functional pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), Gene Ontology (GO), and Reactom visual map. KEGG and GO results showed the metabolism and immune responses were mostly affected by the loss of mtDNA. Moreover, we discovered several interacting genes including POLR2F, HIST1H2BJ, PPP1CC, HOXB4, ARG1, APITD1, BUB1B, POLR2K, HOXC4, and HOXB3 were involved in the regulation of metabolic or cancer diseases. Further, we predicted several regulators that had the ability to affect mitochondria during the dysfunction of mtDNA by L1000fwd analysis. Thus, this study provides further insights into the mechanism of mtDNA in metabolic diseases.

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“…We have now identified SLFN11 as a novel HCMV restriction factor, although the mechanism of restriction is yet to be determined. SLFN11 inhibits replication of lentiviruses in a codon usage-dependent manner, via its activity as a type II tRNA endonuclease (15,16,24,25). Overall, HCMV genomes exhibit low codon usage bias, although the bias of individual coding sequences varies widely (26).…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Nightingale¹,

Fielding

Zerbe³

et al. 2021

Preprint

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Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate and adaptive immunity. We have employed two novel, orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins downregulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterised, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

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Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response

Cited by 34 publications

References 18 publications

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

Identification of biomarkers and pathways of mouse embryonic fibroblasts with the dysfunction of mitochondrial DNA

Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

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