Heterogeneous Nuclear Ribonucleoproteins A1 and A2 Function in Telomerase-Dependent Maintenance of Telomeres.

Tong-Hong Wang,Chin-Chuan Chen,Pei-Rong Huang,Yuan-Chao Hsiao,Chi-Yuan Chen,Yu-Han Lin,Wen-Chieh Pi,Tzu-Chien Wang

doi:10.3390/cancers11030334

Tong-Hong Wang, Chin-Chuan Chen + Show 6 more

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https://doi.org/10.3390/cancers11030334

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Abstract

The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to inhibit cell proliferation and induce apoptosis in cancer cells, but not in mortal normal cells. However, the molecular basis for such a differential inhibition of cell proliferation remains unknown. Here, we show that the simultaneous suppression of hnRNP A1 and hnRNP A2 resulted in dysfunctional telomeres and induced DNA damage responses in cancer cells. The inhibition of apoptosis did not alleviate the inhibition of cell proliferation nor the formation of dysfunctional telomeres in cancer cells depleted of hnRNP A1/A2. Moreover, while proliferation of mortal normal fibroblasts was not sensitive to the depletion of hnRNP A1/A2, the ectopic expression of hTERT in normal fibroblasts rendered these cells sensitive to proliferation inhibition, which was associated with the production of dysfunctional telomeres. Our study demonstrates that hnRNP A1 and A2 function to maintain telomeres in telomerase-expressing cells only, suggesting that the maintenance of functional telomeres in telomerase-expressing cancer cells employs factors that differ from those used in the telomerase-negative normal cells.

Highlights

Telomeres are specialized structures found at the ends of chromosomes in eukaryotic cells.Human telomeres contain repeats of the sequence CCCTAA/TTAGGG, varying in length from 2 to 50 kilobase pairs, and a short single-stranded G-rich 30 overhang
In view of recent findings establishing an important role for Heterogeneous nuclear ribonucleoproteins (hnRNPs) A1 and A2 in telomere maintenance [30,31], it is likely that the functional redundancy of hnRNP A1 and A2 in cell proliferation may be related to their role in maintaining functional telomeres
We examined whether DNA damage response (DDR) is induced by the depletion of hnRNP A1 or A2, since it is known to be triggered by dysfunctional telomeres

Summary

Introduction

Telomeres are specialized structures found at the ends of chromosomes in eukaryotic cells. Human telomeres contain repeats of the sequence CCCTAA/TTAGGG, varying in length from 2 to 50 kilobase pairs, and a short single-stranded G-rich 30 overhang. DNA is tightly associated with a complex of 6 telomere-specific proteins (POT1, TRF1, TRF2, TPP1, RAP1, and TIN2) known as the shelterin complex, and with surrounding chromatin regulatory factors [1,2,3]. Cancers 2019, 11, 334 kinases, triggering growth arrest, senescence, and apoptosis, as well as increasing end-to-end fusions and anaphase bridges [3]. Dysfunctional telomeres are produced through various mechanisms. Telomere attrition represents a normal mechanism that limits the replicative potential of human somatic cells and can serve as a tumor-suppressor pathway in potential cancer cells

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