PARN Knockdown in Cell Lines Results in Differential and Cell-Specific Alterations in the Expression of Cancer-Associated mRNAs

Babu, Nishith; Nanjappa, Dechamma Pandyanda; Nazareth, Sandra Celenia; Arjuna, Srividya; Chakraborty, Anirban

doi:10.31557/apjcp.2022.23.1.207

Cited by 3 publications

(3 citation statements)

References 27 publications

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“…In lung cancer, overexpression of CNOT6 predicts better patient survival outcomes, where patients with elevated CNOT6 expression are less likely to develop metastasis (Maragozidis et al 2015). PARN was reported to be downregulated in lung cancer cell lines, and PARN depletion does not impact proliferation of lung cancer cells (Babu et al 2022). However, it was found that PARN expression is upregulated, especially in young patients (Maragozidis et al 2015), suggesting that there are age-specific factors that contribute to the disease.…”

Section: Cancersmentioning

confidence: 99%

RNA deadenylation complexes in development and diseases

Liu

Ramkumar

2023

Biochem. Cell Biol.

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RNA deadenylation, the process of shortening of the 3’ poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.

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Section: Cancersmentioning

confidence: 99%

RNA deadenylation complexes in development and diseases

Liu

Ramkumar

2023

Biochem. Cell Biol.

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“…The role of TP53 in mediating apoptosis of the primordial germ cells has been suggested as the possible mechanism in all-male phenotype in atm and fancl null zebrafish. Interestingly, we have shown that downregulation of PARN in cell lines reduces TP53 transcript levels 23 . Thus, it would be interesting to see if the TP53 pathway is responsible for impaired oogenesis in parn null mutants as seen in atm and fancl null mutants.…”

Section: Discussionmentioning

confidence: 88%

“…It is also found to be mutated in several diseases associated with telomere dysfunction and in genetic conditions involving bone marrow failures 9 , 20 , 21 . Also, our previous studies showed that PARN is consistently downregulated in non-small cell lung cancers 22 and PARN depletion in cell lines results in differential and cell-specific alterations in the expression of various tumor suppressor and oncogene mRNAs 23 . Given the fact that PARN is now considered a protein that has multiple roles in cells besides just mRNA stock clearing 5 , development of an alternative animal model to systematically examine the effects of complete loss of PARN was very much warranted as the previous attempt to generate Parn -null mice was unsuccessful 12 .…”

Section: Discussionmentioning

confidence: 90%

Poly (A)-specific ribonuclease deficiency impacts oogenesis in zebrafish

Nanjappa

Saffel

Kalladka

et al. 2023

Sci Rep

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Poly (A)-specific ribonuclease (PARN) is the most important 3′–5′exonuclease involved in the process of deadenylation, the removal of poly (A) tails of mRNAs. Although PARN is primarily known for its role in mRNA stability, recent studies suggest several other functions of PARN including a role in telomere biology, non-coding RNA maturation, trimming of miRNAs, ribosome biogenesis and TP53 function. Moreover, PARN expression is de-regulated in many cancers, including solid tumours and hematopoietic malignancies. To better understand the in vivo role of PARN, we used a zebrafish model to study the physiological consequences of Parn loss-of-function. Exon 19 of the gene, which partially codes for the RNA binding domain of the protein, was targeted for CRISPR-Cas9-directed genome editing. Contrary to the expectations, no developmental defects were observed in the zebrafish with a parn nonsense mutation. Intriguingly, the parn null mutants were viable and fertile, but turned out to only develop into males. Histological analysis of the gonads in the mutants and their wild type siblings revealed a defective maturation of gonadal cells in the parn null mutants. The results of this study highlight yet another emerging function of Parn, i.e., its role in oogenesis.

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Poly(A)-Specific Ribonuclease Deficiency Leads to Deregulated Expression of Genes Involved in Sex Determination and Gonadal Maturation in Zebrafish

Felicitus,

Nanjappa,

Kalladka

et al. 2024

Journal of Health and Allied Sciences NU

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Background Deadenylation, the process of removal of poly (A) tail of messenger ribonucleic acids (mRNAs), is a rate-limiting step in mRNA stability, and poly(A)-specific ribonuclease (PARN) is the most important exonuclease involved in this process. Besides mRNA stability, PARN is also involved in several other processes including telomere maintenance, noncoding RNA maturation, ribosome biogenesis, and TP53 function. Previously, we have shown that zebrafish PARN null mutants are viable and fertile but turn out to only develop into males, indicating a role in oogenesis. The present study was focused on analyzing the expression of genes involved in sex determination and gonadal development in PARN mutant zebrafish. Materials and Methods Total RNA was extracted and quantitative real-time polymerase chain reaction was performed to determine the expression level of genes involved in gonad development in PARN mutant embryos (4 days postfertilization [dpf]) and adults (120 dpf) in comparison to their wild-type siblings. The expression levels were estimated by the ΔΔCT relative quantification method. Results At 4 dpf, the expression of germ cell-specific genes did not show any significant difference in the null mutants compared to the heterozygous and their wild-type siblings, suggesting no effect on germ cell differentiation due to the loss of PARN. However, the majority of the ovary-associated genes analyzed showed an increased expression in PARN null and heterozygous mutants compared to the wild-type siblings. Intriguingly, the expression of testis-associated genes showed decreased expression in the mutants compared to their wild-type siblings at 4 dpf. In adult stages, as expected, the expression of genes that jointly regulate the proper formation and function of ovaries and testes showed decreased expression in PARN null mutants. Interestingly, the expression of genes involved in the differentiation of testes, despite showing a decreased expression in the mutants, was comparable between the null and heterozygous mutants. Conclusion Taken together, these results suggest that the loss of PARN does not affect germ cell differentiation but affects the sexual differentiation that happens at later stages of development, particularly the process of oogenesis, in zebrafish.

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PARN Knockdown in Cell Lines Results in Differential and Cell-Specific Alterations in the Expression of Cancer-Associated mRNAs

Cited by 3 publications

References 27 publications

RNA deadenylation complexes in development and diseases

RNA deadenylation complexes in development and diseases

Poly (A)-specific ribonuclease deficiency impacts oogenesis in zebrafish

Poly(A)-Specific Ribonuclease Deficiency Leads to Deregulated Expression of Genes Involved in Sex Determination and Gonadal Maturation in Zebrafish

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