Telomeres and marrow failure
- 1 January 2009
- journal article
- review article
- Published by American Society of Hematology in Hematology
- Vol. 2009 (1), 338-343
- https://doi.org/10.1182/asheducation-2009.1.338
Abstract
Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3′ ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals—all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.Keywords
This publication has 39 references indexed in Scilit:
- Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibilityLung Cancer, 2009
- Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemiaProceedings of the National Academy of Sciences of the United States of America, 2009
- TINF2 mutations in children with severe aplastic anemiaPediatric Blood & Cancer, 2008
- Lung cancer susceptibility locus at 5p15.33Nature Genetics, 2008
- Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenitaProceedings of the National Academy of Sciences of the United States of America, 2008
- TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis CongenitaAmerican Journal of Human Genetics, 2008
- Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndromeBlood, 2007
- Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenitaBlood, 2007
- Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10Human Molecular Genetics, 2007
- Adult-onset pulmonary fibrosis caused by mutations in telomeraseProceedings of the National Academy of Sciences of the United States of America, 2007