Telomere end-replication problem and cell aging

Levy, M. Z., Allsopp, R. C., Futcher, A. B., Greider, C. W., Harley, C. B. (June 1992) Telomere end-replication problem and cell aging. J Mol Biol, 225 (4). pp. 951-60. ISSN 0022-2836 (Print)0022-2836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/1613801
DOI: 10.1016/0022-2836(92)90096-3

Abstract

Since DNA polymerase requires a labile primer to initiate unidirectional 5'-3' synthesis, some bases at the 3' end of each template strand are not copied unless special mechanisms bypass this "end-replication" problem. Immortal eukaryotic cells, including transformed human cells, apparently use telomerase, an enzyme that elongates telomeres, to overcome incomplete end-replication. However, telomerase has not been detected in normal somatic cells, and these cells lose telomeres with age. Therefore, to better understand the consequences of incomplete replication, we modeled this process for a population of dividing cells. The analysis suggests four things. First, if single-stranded overhangs generated by incomplete replication are not degraded, then mean telomere length decreases by 0.25 of a deletion event per generation. If overhangs are degraded, the rate doubles. Data showing a decrease of about 50 base-pairs per generation in fibroblasts suggest that a full deletion event is 100 to 200 base-pairs. Second, if cells senesce after 80 doublings in vitro, mean telomere length decreases about 4000 base-pairs, but one or more telomeres in each cell will lose significantly more telomeric DNA. A checkpoint for regulation of cell growth may be signalled at that point. Third, variation in telomere length predicted by the model is consistent with the abrupt decline in dividing cells at senescence. Finally, variation in length of terminal restriction fragments is not fully explained by incomplete replication, suggesting significant interchromosomal variation in the length of telomeric or subtelomeric repeats. This analysis, together with assumptions allowing dominance of telomerase inactivation, suggests that telomere loss could explain cell cycle exit in human fibroblasts.

Item Type: Paper
Uncontrolled Keywords: Adult Base Sequence Cell Division Cells, Cultured Chromosome Deletion Chromosomes, Human/*physiology DNA/genetics/*metabolism *DNA Replication Fibroblasts/cytology/physiology Humans Kinetics Models, Genetic Oligonucleotide Probes Repetitive Sequences, Nucleic Acid Skin Physiological Phenomena Telomere/*physiology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA replication
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal deletions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosome
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function > chromosome

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > telomeres
CSHL Authors:
Communities: CSHL labs > Futcher lab
CSHL labs > Greider lab
Depositing User: Matt Covey
Date: 20 June 1992
Date Deposited: 30 Sep 2015 19:16
Last Modified: 30 Sep 2015 19:16
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31806

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