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Alternative Polyadenylation of PRELID1 Regulates Mitochondrial ROS Signaling and Cancer Outcomes.

ABSTRACT: Disruption of posttranscriptional gene regulation is a critical step in oncogenesis that can be difficult to observe using traditional molecular techniques. To overcome this limitation, a modified polyadenylation site sequencing (PAS-seq) protocol was used to generate a genome-wide map of alternative polyadenylation (APA) events in human primary breast tumor specimens and matched normal tissue. This approach identified an APA event in the PRELID1 mRNA that enhances its steady-state level and translational efficiency, and is a strong breast cancer subtype-dependent predictor of patient clinical outcomes. Furthermore, it has been demonstrated that PRELID1 regulates stress response and mitochondrial reactive oxygen species (ROS) production in a cell type-specific manner. Modulation of PRELID1 expression, including its posttranscriptional control, appears to be a common stress response across different cancer types. These data reveal that PRELID1 mRNA processing is an important regulator of cell type-specific responses to stress used by multiple cancers and is associated with patient outcomes.Implications: This study suggests that the regulation of PRELID1 expression, by APA and other mechanisms, plays a role in mitochondrial ROS signaling and represents a novel prognostic factor and therapeutic target in cancer. Mol Cancer Res; 15(12); 1741-51. ©2017 AACR.

SUBMITTER: Gillen AE

PROVIDER: S-EPMC5791535 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Alternative Polyadenylation of <i>PRELID1</i> Regulates Mitochondrial ROS Signaling and Cancer Outcomes.

Gillen Austin E AE Brechbuhl Heather M HM Yamamoto Tomomi M TM Kline Enos E Pillai Manoj M MM Hesselberth Jay R JR Kabos Peter P

Molecular cancer research : MCR 20170914 12

Disruption of posttranscriptional gene regulation is a critical step in oncogenesis that can be difficult to observe using traditional molecular techniques. To overcome this limitation, a modified polyadenylation site sequencing (PAS-seq) protocol was used to generate a genome-wide map of alternative polyadenylation (APA) events in human primary breast tumor specimens and matched normal tissue. This approach identified an APA event in the <i>PRELID1</i> mRNA that enhances its steady-state level ...[more]

PMID: 28912168

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Project description:BackgroundPolyadenylation is a crucial process that terminates mRNA molecules at their 3'-ends. It has been observed that alternative polyadenylation (APA) can generate multiple transcripts from a single gene locus, each with different polyadenylation sites (PASs). This leads to the formation of several 3' untranslated regions (UTRs) that vary in length and composition. APA has a significant impact on approximately 60-70% of eukaryotic genes and has far-reaching implications for cell proliferation, differentiation, and tumorigenesis.ResultsIn this study, we conducted long-read, single-molecule sequencing of mRNA from peanut seeds. Our findings revealed that over half of all peanut genes possess over two PASs, with older developing seeds containing more PASs. This suggesting that the PAS exhibits high tissue specificity and plays a crucial role in peanut seed maturation. For the peanut acetyl-CoA carboxylase A1 (AhACCA1) gene, we discovered four 3' UTRs referred to UTR1-4. RT-PCR analysis showed that UTR1-containing transcripts are predominantly expressed in roots, leaves, and early developing seeds. Transcripts containing UTR2/3 accumulated mainly in roots, flowers, and seeds, while those carrying UTR4 were constitutively expressed. In Nicotiana benthamiana leaves, we transiently expressed all four UTRs, revealing that each UTR impacted protein abundance but not subcellular location. For functional validation, we introduced each UTR into yeast cells and found UTR2 enhanced AhACCA1 expression compared to a yeast transcription terminator, whereas UTR3 did not. Furthermore, we determined ACC gene structures in seven plant species and identified 51 PASs for 15 ACC genes across four plant species, confirming that APA of the ACC gene family is universal phenomenon in plants.ConclusionOur data demonstrate that APA is widespread in peanut seeds and plays vital roles in peanut seed maturation. We have identified four 3' UTRs for AhACCA1 gene, each showing distinct tissue-specific expression patterns. Through subcellular location experiment and yeast transformation test, we have determined that UTR2 has a stronger impact on gene expression regulation compared to the other three UTRs.

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Alternative Polyadenylation of PRELID1 Regulates Mitochondrial ROS Signaling and Cancer Outcomes.

Publications

Alternative Polyadenylation of <i>PRELID1</i> Regulates Mitochondrial ROS Signaling and Cancer Outcomes.

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