Atlas of Genetics and Cytogenetics in Oncology and Haematology

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I. Mammalian Telomere Structure
I.1. DNA Sequence
I.2. t-loops, G-loops, D-loops
I.3. Protein Components
II. Telomere Function
II.1. Chromosome Stability
II.2. Cell Division Counter
II.3. Mechanism for Replicating DNA Ends
II.4. Chromosome Integrity
III. Telomere Maintenance
III.1. Telomerase

III.2. Telomere-Independent/Alternative Lengthening of Telomeres (ALT)
IV. Senescence and Immortalization
IV.1. Hayflick Limit

IV.2. Telomeres and Telomerase

IV.3. Immortalization
V. Aging
V.1. Role of Telomere Length

V.2. Role of ATM

V.3. Human Disorders of Premature Aging

V.4. Telomere Position Effect (TPE)
VI. Genomic Instability and Neoplasias
VI.1. Role of Telomere Length

VI.2. Expression of Telomerase

VI.3. Chromosome and Genomic Instability



All eukaryotic chromosomes are capped by telomeres, structures composed of DNA and associated proteins comprising the ends of each linear chromosome.


I.1. DNA Sequence


I.2. t-loops, G-loops, D-loops


I.3. Protein Components

Telomere binding proteins include:

I.3.1. TRF1 (telomeric repeat binding factor 1)

I.3.2. TRF2 (telomeric repeat binding factor 2)

I.3.3. hRAP1

I.3.4. TIN2 (TRF1-interacting nuclear factor 2)

I.3.5. TANK1/TNKS (tankyrase, TRF1-interacting ankyrin-related polymerase)

N.B. Therefore, telomere function can be compromised by affecting telomere-binding protein function(s).




II.1. Confer Stability and Protect Chromosome Ends


II.2. Count Number of Cell Divisions



III.1. Telomerase

III.1.1. RNA Component: hTERC (human telomerase encoded RNA)


III.1.2. Catalytic Component: hTERT (human telomere reverse transcriptase)


III.1.3. Mechanism



III.2. Telomerase independent/alternative lengthening of telomeres (ALT)

III.2.1. Length of telomeres synthesized by ALT is characteristically heterogeneous

III.2.2. Telomere length is dynamic, changes regularly

III.2.3. Active in telomerase negative neoplasias (~10-15% of all neoplasias)

III.2.4. Preferentially active in mesenchymally-derived cells, compared with those of epithelial origin

III.2.5. Repressors of ALT expressed in normal cells and in certain telomerase negative cells (i.e., ALT activity and telomerase activity can co-exist in the same cells)

III.2.6. Proportion of ALT(+) cells are associated with PML bodies (promyelocytic leukemia nuclear body, or PML NB)

III.2.7. Mechanism of ALT likely involves homologous recombination between telomeres; sequences copied from a single telomere to another by complementary annealing as a means of priming new telomeric DNA

III.2.8. G-loop vs. t-loop, D-loop (see above for description of roles)

III.2.9. Experiments performed in yeast :




IV.1. Hayflick Limit (1961)


IV.2. Telomeres and Telomerase

IV.2.1. Telomeres hold a critical function in cellular senescence

IV.2.2. Telomeres count the number of cell divisions

IV.2.3. Telomerase can reset the cell division counter :

IV.2.4. Two biological impediments to extended lifespan of human cells :

a. M1: replicative senescence, or mortality stage 1 (function is to inhibit cellular immortalization)

b. M2: crisis (cells in crisis usually enter apoptotic pathway, those that can elude crisis stage become immortal). These cells:

1. Express telomerase
2. Show relatively constant telomere lengths
3. Show aneuploidy
4. Show non-reciprocal translocations
5. Together, these data suggest that at crisis stage, telomeres lose protective abilities

IV.2.5. Expression of telomerase in primary (human) cells

IV.2.6. Sufficient damage sustained by telomeres

IV.2.7. Telomere-length threshold capable of initiating senescence


IV.3. Immortalization




V.1. Role of Telomere Length


V.2. Role of ATM


V.3. Human Disorders of Premature Aging

Genetic aberrations that increase rates of telomere erosion and inhibit normal DNA repair from occurring at the telomere synergize to cause premature aging, a phenomenon seen in several disorders that feature predisposition to neoplasias.




VI.1. Role of Telomere Length


VI.2. Expression of Telomerase

VI.1.1. Reactivation of telomerase expression directly correlates with neoplasias, supporting the notion that telomeres and telomere maintenance are central to the formation of cancers

VI.1.2. Expression of hTERT alone causes immortalization alone; cell transformation requires immortalization accompanied by inactivation of tumor suppressor genes and activation of cellular oncogenes

VI.1.3. Telomere shortening can serve to inhibit early stages of tumor growth; however, telomere shortening, particularly in the context of a dysregulated cell cycle, can facilitate neoplasia by:

VI.1.4. Recent data suggest telomerase reactivation contributes to neoplasia through pathways independent of telomere maintenance

VI.3. Chromosome and Genomic Instability

VI.3.1. Molecular and cytogenetic studies have indicated chromosomes with even a single unprotected chromosome end are genetically unstable until telomere integrity has been restored. During this period of genetic instability, breakage-fusion-breakage (BFB) cycles occur, often culminating in chromosomal aneuploidies

VI.3.2. BFB cycles and chromosomal instability also promote sister chromatid fusions through non-homologous end joining (NHEJ)

VI.3.3. During mitosis, separation of centromeres in dicentric chromosomes to opposite poles produces an anaphase bridge, followed by chromosome breakage, subsequent fusion of damaged ends, and promotion of additional BFB cycles

VI.3.4. Recurring cycles of gene amplification can arise during acquisition of new telomeres by rearranged chromosomes, suggesting double-stranded DNA breaks are important in promoting amplification of genes closest to a chromosomal break

VI.3.5. In order to survive, genetically unstable cells also must escape detection by cell-cycle regulators, such as p53, which can induce growth arrest or apoptosis in response to damaged DNA


Contributor : Azra H. Ligon


Written2004-04Azra H. Ligon
Brigham &Women's Hospital, Department of Pathology, 75 Francis Street, Boston MA 02115, USA

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Nov 13 20:40:10 CET 2019

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