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TENT4A non-canonical poly(A) polymerase regulates DNA-damage tolerance via multiple pathways which are mutated in endometrial cancer

ABSTRACT: TENT4A non-canonical poly(A) polymerase regulates DNA-damage tolerance via multiple pathways which are mutated in endometrial cancer

PROVIDER: PRJNA594987 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10673583.fastq.gz	Fastqsanger.gz
	SRR10673584.fastq.gz	Fastqsanger.gz
	SRR10673585.fastq.gz	Fastqsanger.gz
	SRR10673586.fastq.gz	Fastqsanger.gz
	SRR10673587.fastq.gz	Fastqsanger.gz

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TENT4A non-canonical poly(A) polymerase regulates DNA-damage tolerance via multiple pathways which are mutated in endometrial cancer

Project description:TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here we show that TENT4A is involved in the regulation of multiple biological pathways, and focus on translesion DNA synthesis (TLS), a DNA-damage tolerance process in which unrepaired lesions are bypassed by error-prone DNA polymerases. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η, and of the RAD18 E3 ligase that monoubiquitinates PCNA, the latter being a key step in TLS which enables recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD, and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or over-expression of PAXIP1-AS2 led each to a decrease in the amount of the RAD18 protein, but the effect on PCNA ubiquitination was variable. Still, TLS was reduced under these conditions, likely due a to a parallel decrease in DNA polymerase η. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in endometrial cancer.

2021-06-29 | GSE141870 | GEO

TENT4A Non-Canonical Poly(A) Polymerase Regulates DNA-Damage Tolerance via Multiple Pathways That Are Mutated in Endometrial Cancer.

Project description:TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here, we show that TENT4A regulates multiple biological pathways and focuses on its multilayer regulation of translesion DNA synthesis (TLS), in which error-prone DNA polymerases bypass unrepaired DNA lesions. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η and RAD18 E3 ligase, which guides the polymerase to replication stalling sites and monoubiquitinates PCNA, thereby enabling recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or overexpression of PAXIP1-AS2 led each to reduced amounts of the RAD18 protein and DNA polymerase η, leading to reduced TLS, highlighting PAXIP1-AS2 as a new TLS regulator. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in this cancer.

| S-EPMC8267958 | biostudies-literature

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis

| PRJNA1029581 | ENA

The FAM46C gene encodes a non-canonical poly(A) polymerase and acts as an onco-suppressor in multiple myeloma

Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM) and encodes a protein of unknown function. Using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active cytoplasmic non-canonical poly(A) polymerase, which enhances mRNA stability and gene expression. Moreover, we also found that the reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induced cell death. This is, to our knowledge, the first report that directly associates cytoplasmic poly(A) polymerase with carcinogenesis. Furthermore, our data suggest that the human genome encodes at least eleven non-canonical poly(A) polymerases with four FAM46 family members. Since FAM46 proteins are differentially expressed during development, these proteins may positively regulate transcript stability and translational rate in a tissue-specific manner.

2017-06-30 | GSE83772 | GEO

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [RIP]

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [RIP]

| PRJNA1029586 | ENA

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [ADAR_APOBEC]

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [ADAR_APOBEC]

| PRJNA1029583 | ENA

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [RNA-seq]

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [RNA-seq]

| PRJNA1029589 | ENA

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [CUT&RUN]

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [CUT&RUN]

| PRJNA1029588 | ENA

The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [Capture-C]

Project description:The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [Capture-C]

| PRJNA1029582 | ENA

The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma

Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM). Here, using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active non-canonical poly(A) polymerase which enhances mRNA stability and gene expression. Reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death. Moreover, silencing of FAM46C in MM cells expressing WT protein enhance cell proliferation. Finally, using a FAM46C-FLAG knock-in mouse strain we show that the FAM46C protein is strongly induced during activation of primary splenocytes and that B lymphocytes isolated from newly generated FAM46C KO mice proliferate faster than those isolated from their WT littermates. Concluding, our data clearly indicate that FAM46C works as an onco-suppressor, with the specificity for B-lymphocyte lineage from which multiple myeloma originates.

2018-03-09 | PXD006790 | Pride

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