SLFN11, far from being limited to responding to cancer DNA damage

Abstract

SLFN11, a member of the evolutionarily conserved SLFN gene family, is an interferon-stimulated early response gene. This review comprehensively explores its multifaceted roles. Structurally, its three distinct domains endow it with diverse functions. Epigenetic modifications, post-translational alterations, and multiple signaling pathways intricately regulate SLFN11 expression and activity. In terms of functions, it plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways. It also serves as a protector in the antiviral response and a valuable biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers. Beyond these, SLFN11 has non-canonical functions, including immune regulation, modulation of oncological behaviors, involvement in apoptosis, protection against proteotoxic stress, and association with Fanconi anemia. Looking ahead, SLFN11 holds great promise as a biomarker for personalized medicine, but challenges like developing accurate detection methods remain. In immunotherapy, understanding its dynamic changes is essential for optimizing treatment. Strategies to overcome SLFN11-low expression, such as epigenetic modulation, also need further investigation, which may open new avenues for disease treatment.

Keywords: Antiviral function; Biomarker; DNA damage response; Epigenetic modification; Immune regulation; Oncological behavior; Schlafen 11.

Fig. 1

Structure of SLFN11. A The full length of SLFN11 protein is composed of an N-terminal endonuclease domain (1–353), a linker domain (354–576), and a C-terminal helicase domain (577–901). B Three-dimensional structure of SLFN11 protein with a horseshoe-like N-terminal endonuclease domain and an inter-domain helix connecting SWAVDL motif and C-lobe of helicase domain. C The homodimer of SLFN11 protein is bound together by interface I and interface II between the N-lobes of endonuclease domains and helicase domains. D Top view of SLFN11 endonuclease domains which is the tRNA cleaving site. E Bottom view of SLFN11 helicase domains with 5 nucleotides of ssDNA binding to each helicase domain in the opposite direction

Fig. 2

Upstream regulatory mechanism of SLFN11. SLFN11 is regulated by epigenetic modification, post-translational modification and signaling pathways. SLFN11 as an interferon-stimulated gene is activated through canonical JAK1/2-STAT1 pathway. At gene level, several drugs can alter the epigenetic modification of SLFN11 contributing to changes in its expression. In leukemic cells with gain-of-function mutations of JAK, SLFN11 can be activated in non-canonical JAK-AKT/ERK pathway. The interaction between TSP1 and CD47 is observed in specific cancer types. After protein translation, specific serine and threonine can be dephosphorylation which influences its ability of binding to ssDNA or cleaving tRNA

Fig. 3

The SLFN11 performs its canonical function. Anti-virus. SLFN11 itself can be regulated by type I interferons, up-regulating its own expression levels through the JAK1/2-STAT1/2 pathway and IRF3/7. SLFN11 inhibits translation initiation mainly through direct binding to tRNAs in a codon-usage-based manner, and can inhibit tRNA pool alterations. HCMV-RL1 recruits CRL4, which promotes ubiquitination-mediated degradation of SLFN11, thereby resisting the antiviral response to SLFN11. DDR responder. When DNA damage occurs, SLFN11 and ATR are simultaneously recruited to the site of damage at an early stage (< 4 h), along with MCM and RPA. ATR can activate CHK1 thereby inhibiting CDC45 and PCNA activity. In the late stage (> 24 h), SLFN11 induces an irreversible replication block, which is independent of ATR, and SLFN11 can block translation of ATR and ATM by shearing specific tRNAs. SLFN11 also promotes chromatin opening and expression of IEGs. SLFN11 binds to DDB1 of CUL4^CDT2 E3 ubiquitin ligase complex to promote the degradation of CDT1 and inhibit the occurrence of unscheduled replication. MLN-4924, a neddylation inhibitor can promote the recruitment of SLFN11 in this process. DDAs sensitivity biomarker. Application of DDAs in SLFN11-expressing tumor cells results in greater sensitivity to the drug. Prognostic biomarker. SLFN11 can be used as a powerful prognostic marker in different cancers occurring in multiple organs of the human body

Fig. 4

The SLFN11 performs its non-canonical function. A SLFN11 acts as immunity regulator. Its expression is upregulated by JAK1/2—STAT1/2 and IRF3/7. DNA damage activates ERK, MAPK pathways and IEGs, and SLFN11, acting as a nucleic acid receptor, senses ssDNA. Binding of its C—terminal to the CGT motif of ssDNA triggers translocation to the cytoplasm, where its N—terminal RNase activity cleaves tRNA, activating inflammation, apoptosis, and the innate immune system. AAV—derived ssDNA also induces these processes. B SLFN11 acts as oncology behavior. In oncology, SLFN11 interacts with IFN—γ and DDAs, influencing cancer cell sensitivity to T—cell killing. In different cancers, it either promotes or inhibits tumor development by modulating various signaling pathways. For example, in glioblastoma and clear cell renal cell carcinoma, it promotes growth, while in hepatocellular carcinoma, it inhibits tumor progression. It also impacts immune—related processes like macrophage polarization. C SLFN11 regulates p53-independent apoptosis. SLFN11 responds to the DDR by cleaving the tRNA^UUA, which causes ribosome stalling at the UUA during translation initiation, leading to the onset of the ribotoxic stress response and the integrated stress response. In the ribotoxic stress response, ZAKα is activated to activate downstream MAP2K4 and JNK, which leads to p53-independent apoptosis. In the integrated stress response, GCN2 is activated and phosphorylates eIF2a, leading to global translation inhibition. D SLFN11 inhibits misfolded proteins by binding to translation initiation complex proteins and protein folding complex proteins (CCT chaperonin and TRiC), which inhibit ER stress, ERAD and UPR, and inhibits Claspin-CHK1-mediated replication pausing. The UBA1 inhibitor TAK-2 promotes apoptosis and cell cycle arrest in SLFN11-deficient cells. E In Fanconi anemia cells, SLFN11 inhibits the recruitment of RAD51 to stalled replication forks and leads to degradation of replication forks by nuclease DNA2 and MRE11, whereas in SLFN11-deficient cells, the phenotype can revert