A Novel Tissue and Stem Cell Specific TERF1 Splice Variant Is Downregulated in Tumour Cells

Abstract

In this study, we describe the identification of a novel splice variant of TERF1/PIN2, one of the main components of the telomeric shelterin complex. This new splice variant is identical to TERF1, apart from a 30 amino acid internal insertion near to the C-terminus of TERF1. Based on genome comparison analyses and RNA expression data, we show that this splice variant is conserved among hominidae but absent from all other species. RNA expression and histological analyses show specific expression in human spermatogonial and hematopoietic stem cells (HSCs), while all other analyzed tissues lack the expression of this TERF1-isoform, hence the name TERF1-tsi (TERF1-tissue-specific-isoform). In addition, we could not detect any expression in primary human cells and established cancer cell lines. Immunohistochemistry results involving two new rabbit polyclonal antibodies, generated against TERF1-tsi specific peptides, indicate nuclear localization of TERF1-tsi in a subset of spermatogonial stem cells. In line with this observation, immunofluorescence analyzes in various cell lines consistently revealed that ectopic TERF1-tsi localizes to the cell nucleus, mainly but not exclusively at telomeres. In a first attempt to evaluate the impact of TERF1-tsi in the testis, we have tested its expression in normal testis samples versus matched tumor samples from the same patients. Both RT-PCR and IHC show a specific downregulation of TERF1-tsi in tumor samples while the expression of TERF1 and PIN2 remains unchanged.

The Influence of Telomere-Related Gene Variants, Serum Levels, and Relative Leukocyte Telomere Length in Pituitary Adenoma Occurrence and Recurrence

“…However, previous research, as highlighted by Bhari et al, has linked high expression levels of both TERF1 and TERF2 to a poor prognosis in breast cancer, suggesting their potential as prognostic markers in cancer [25]. Additionally, the work of Marcos and colleagues has indicated that TERF1 is deregulated in the context of cancer development, underscoring its relevance in the broader field of oncology [26].…”

Role of Telomeres and Telomerase in Cancer and Aging

“…Morcos et al analysed the telomeric shelterin protein TERF1/Pin2 and found that a new splice version of it is downregulated specifically in testis-derived cancer cells [ 18 ]. TERF1 is involved in telomere length regulation with a specific role in the S-phase during replication fork movement.…”

“…The new splice version possesses a 30-amino-acid internal insertion near to the C-terminus of TERF1 and is preferentially expressed in human spermatogonial and hematopoietic stem cells, and thus is strongly tissue-specific and was named TERF-tsi. In contrast, primary human cells or established cancer cell lines did not express this factor [ 18 ]. The authors demonstrated that while normal TERF1 and its splice variant PIN2 persisted during testis-derived tumourigenesis, TERF-tsi was specifically downregulated in this process, suggesting a function as a tumour suppressor for this new splice version.…”