Abstract
Telomeres are protective repeats of TTAGGG sequences located at the end of human chromosomes. They are essential to maintain chromosomal integrity and genome stability. Telomerase is a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic subunit (hTERT). The human hTR gene consists of three major domains; among them the H/ACA domain is essential for telomere biogenesis. H/ACA ribonucleoprotein (RNP) complex is composed of four evolutionary conserved proteins, including dyskerin (encoded by DKC1 gene), NOP10, NHP2 and GAR1. In this study, we have evaluated the expression profile of the H/ACA RNP complex genes: DKC1, NOP10, NHP2 and GAR1, as well as hTERT and hTR mRNA levels, in patients with chronic lymphocytic leukemia (CLL). Results were correlated with the number and type of genetic alteration detected by conventional cytogenetics and FISH (fluorescence in situ hybridization), IGHV (immunoglobulin heavy chain variable region) mutational status, telomere length (TL) and clinico-pathological characteristics of patients. Our results showed significant decreased expression of GAR1, NOP10, DKC1 and hTR, as well as increased mRNA levels of hTERT in patients compared to controls (p≤0.04). A positive correlation between the expression of GAR1-NHP2, GAR1-NOP10, and NOP10-NHP2 (p<0.0001), were observed. The analysis taking into account prognostic factors showed a significant increased expression of hTERT gene in unmutated-IGHV cases compared to mutated-CLL patients (p = 0.0185). The comparisons among FISH groups exhibited increased expression of DKC1 in cases with two or more alterations with respect to no abnormalities, trisomy 12 and del13q14, and of NHP2 and NOP10 compared to those with del13q14 (p = 0.03). The analysis according to TL showed a significant increased expression of hTERT (p = 0.0074) and DKC1 (p = 0.0036) in patients with short telomeres compared to those with long TL. No association between gene expression and clinical parameters was found. Our results suggest a role for these telomere associated genes in genomic instability and telomere dysfunction in CLL.
Highlights
Telomeres are protective repeats of TTAGGG sequences located at the end of chromosomes [1]
The analysis showed a decreased expression of RNP complex genes in chronic lymphocytic leukemia (CLL) patients compared to normal controls (NC), with significant differences for: GAR1 (p = 0.0156), DKC1 (p = 0.0025) and NOP10 (p = 0.0048)
It is important to pointing out that, to our knowledge, this is the first analysis of GAR1, NHP2, NOP10 and human telomerase RNA component (hTR) in this pathology
Summary
Telomeres are protective repeats of TTAGGG sequences located at the end of chromosomes [1]. As described in detail previously [6] human hTR extends for 451 nucleotides, the last 240 at the 3 ́end form a consensus H/ACA two hairpin structure while the 5’ half folds into a pseudoknot containing the template for the reverse transcriptase While it is not needed for telomerase activity in vitro, the H/ACA domain of hTR is required for its in vivo accumulation and stability [6, 7]. H/ACA RNPs consist of four evolutionarily conserved proteins, Dyskerin [encoded by the gene DKC1 (Dyskerin Pseudouridine Synthase 1)], NHP2 (NHP2 ribonucleoprotein), NOP10 (NP10 ribonucleoprotein), and GAR1 (GAR1 ribonucleoprotein), and a function-specifying, noncoding H/ACA RNAs [8, 9]. Point mutations in DKC1 gene cause the X-linked form of dyskeratosis congenital, a disease with increased predisposition to cancer
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