Functions and evolution of FAM111 serine proteases

Welter, Allison L.; Machida, Yuichi

doi:10.3389/fmolb.2022.1081166

Cited by 18 publications

(30 citation statements)

References 81 publications

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“…Although several m 6 A modification sites were also predicted in FAM111A transcript, m 6 A modification did not post‐transcriptionally regulate FAM111A transcript stability. FAM111A is a single‐stranded DNA‐binding serine protease, which promotes DNA synthesis 53 . FAM111A was also reported as a replication factor needed for PCNA loading during DNA replication 46 .…”

Section: Discussionmentioning

confidence: 99%

N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

Huang

et al. 2023

Cancer Science

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As an epitranscriptomic modulation manner, N6‐methyladenosine (m6A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m6A modification affects the fate of RNAs. The potential contributions of m6A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A‐DT as an m6A‐modified RNA and confirmed three m6A sites on FAM111A‐DT. The m6A modification level of FAM111A‐DT was increased in HCC tissues and cell lines, and increased m6A level was correlated with poor survival of HCC patients. m6A modification increased the stability of FAM111A‐DT transcript, whose expression level showed similar clinical relevance to that of the m6A level of FAM111A‐DT. Functional assays found that only m6A‐modified FAM111A‐DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m6A sites on FAM111A‐DT abolished the roles of FAM111A‐DT. Mechanistic investigations found that m6A‐modified FAM111A‐DT bound to FAM111A promoter and also interacted with m6A reader YTHDC1, which further bound and recruited histone demethylase KDM3B to FAM111A promoter, leading to the reduction of the repressive histone mark H3K9me2 and transcriptional activation of FAM111A. The expression of FAM111A was positively correlated with the m6A level of FAM111A‐DT, and the expression of methyltransferase complex, YTHDC1, and KDM3B in HCC tissues. Depletion of FAM111A largely attenuated the roles of m6A‐modified FAM111A‐DT in HCC. In summary, the m6A‐modified FAM111A‐DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 99%

N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

Huang

et al. 2023

Cancer Science

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“… 30 , 31 Accumulating evidence in recent years has shown that FAM111B mutation is associated with increased susceptibility to malignancy. 7 , 32 Overexpression of FAM111B in cancer cells has been associated with accelerated cancer progression and poor clinical outcomes. 8 , 9 It is still unknown if FAM111B can regulate the development of various malignancies through known or unidentified molecular mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Pan-Cancer Analysis of the Tumorigenic Effect and Prognostic Diagnostic Value of FAM111B in Human Carcinomas

Wu¹,

Liang²

2023

IJGM

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Introduction FAM111B (FAM111 trypsin-like peptidase B) gene mutations have been linked to a hereditary fibrosing poikiloderma disorder known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). Overexpression of FAM111B has been associated with an increased risk of certain cancers with a poor prognosis, although the relationship between FAM111B and other tumors is still unclear, and the molecular mechanism of its action is not fully understood. Methods We investigated the biological functions of FAM111B in 33 solid tumors using multi-omics data. We further recruited 109 gastric cancer (GC) patients for a clinical cohort study to confirm the effect of FAM111B on early tumor recurrence. Furthermore, we assessed the role of FAM111B in GC cell proliferation and migration via EdU incorporation, CCK8 and transwell assays in vitro. Results We found that FAM111B can enhance oncogenesis and progression in multiple tumor types. The clinical cohort of GC showed that upregulation of FAM111B is associated with early recurrence of GC, and knockdown of the FAM111B gene can inhibit the proliferation and migration of GC cells. Gene enrichment analysis indicates that FAM111B promotes cancer through immune system process, chromosome instability, DNA repair, and apoptosis regulation. Mechanistically, FAM111B appears to promote the growth cycle of malignant tumor cells while inhibiting apoptosis. Conclusion FAM111B may serve as a potential pan-cancer biomarker for predicting the prognosis and survival of malignant tumor patients. Our study elucidates the role of FAM111B in the occurrence and development of various cancers, and highlights the need for future research on FAM111B in cancers.

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“…Moreover, transient transfection of FAM111A in human cells exhibited a strong inhibitory effect on viral DNA replication, viral protein expression, and virus replication， further confirming the antiviral function of FAM111A for SPI-1-lacking VACV. The trypsin-like domain of FAM111A contains a catalytic triad including His385, Aps439, and Ser541 24,25 and a DNA-binding domain that plays essential (which was not certified by peer review) is the author/funder. All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, transient transfection of FAM111A in human cells exhibited a strong inhibitory effect on viral DNA replication, viral protein expression, and virus replication， further confirming the antiviral function of FAM111A for SPI-1-lacking VACV. The trypsin-like domain of FAM111A contains a catalytic triad including His385, Aps439, and Ser541 24,25 and a DNA-binding domain that plays essential roles for its localization at the replication forks 5,23 . FAM111A was also shown to bind to the large T antigen of SV40 and inhibit the formation of the replication center of SV40 mutants, demonstrating its broad antiviral activity for DNA viruses 7 .…”

Section: Discussionmentioning

confidence: 99%

Human FAM111A inhibits vaccinia virus replication by degrading viral DNA-binding protein I3 and is antagonized by poxvirus host range factor SPI-1

Zhu

Gao

Zhang

et al. 2023

Preprint

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Poxviruses are large double-stranded DNA viruses that infect a wide range of animals including humans. Smallpox virus, the most notorious poxvirus, was eradicated globally in the 1970s. Since then, other members of the poxvirus family, such as monkeypox virus (MPXV) are still posing a great threat to public health. Vaccinia virus (VACV) is a prototypic poxvirus and was used as the vaccine strain for smallpox eradication. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified vaccinia virus Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A, a nuclear protein that regulates host DNA replication, was previously identified as a putative target of VACV-ΔSPI-1, which was unable to replicate in human cells unless FAM111A was repressed. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent antiviral factor for VACV-ΔSPI-1 and MVA. Deletion of FAM111A was able to rescue the replication of MVA and VACV-ΔSPI-1. Overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A required its functional serine protease domain and DNA binding domain but not the PCNA-interacting motif. We further discovered that FAM111A translocated into the cytoplasm upon VACV infection and this process was activated through the cGAS-STING signaling pathway. Infection-triggered FAM111A degraded the nuclear pore complex via its serine protease activity, translocated to the cytoplasm, and interacted with and promoted the degradation of virus uncoating factor I3 in a DNA-dependent manner. Interestingly, the serine protease activity of FAM111A was only needed for nuclear export but not I3 degradation. Further analysis suggested I3 was degraded through autophagy. Moreover, VACV SPI-1 was found primarily in the nucleus of infected cells and antagonized FAM111A by prohibiting its nuclear export. Mutations in the SPI-1 reactive-site loop (RSL) abolished its anti-FAM111A activity. SPI-1 from MPXV and lumpy skin disease virus could also inhibit human FAM111A. Our findings reveal the detailed mechanism by which FAM111A functions to restrict a cytoplasmic DNA virus and provide explanations for the immune evasive function of VACV SPI-1.

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Functions and evolution of FAM111 serine proteases

Cited by 18 publications

References 81 publications

N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

Pan-Cancer Analysis of the Tumorigenic Effect and Prognostic Diagnostic Value of FAM111B in Human Carcinomas

Human FAM111A inhibits vaccinia virus replication by degrading viral DNA-binding protein I3 and is antagonized by poxvirus host range factor SPI-1

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Functions and evolution of FAM111 serine proteases

Cited by 18 publications

References 81 publications

N6‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

N6‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

Pan-Cancer Analysis of the Tumorigenic Effect and Prognostic Diagnostic Value of FAM111B in Human Carcinomas

Human FAM111A inhibits vaccinia virus replication by degrading viral DNA-binding protein I3 and is antagonized by poxvirus host range factor SPI-1

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N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

N⁶‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A