Telomeres are double trouble
A new study shows that telomeres actually require DNA repair pathways at two distinct points in the cell cycle.
Genomic stability is maintained because DNA damage and stalled replication forks trigger repair pathways, whereas telomeres are thought to protect the ends of chromosomes from triggering such responses. However, a new study shows that telomeres actually require the damage machinery at two distinct points in the cell cycle.
Several reports have suggested that the DNA damage machinery is required for telomere replication, so Verdun and Karlseder looked in more detail at the timing of replication and the proteins that are associated with it in human cell lines. They used chromatin immunoprecipitation (ChIP) of telomeric proteins in conjunction with a BrdU assay to show that replication occurs at two points in the cell cycle. Further ChIP analysis showed that a different DNA damage signal is triggered by telomeres at each of these points: in the first, stalled replication forks at telomeres are recognized as DNA lesions by the ATR (ataxia telangiectasia and Rad3 related)-dependent damage machinery; in the second, the blunt ends of replicating telomeres are recognized as double-strand breaks and the homologous recombination machinery is triggered by ATM (ataxia telangiectasia mutated)-dependent signalling.
The authors used in vitro assays to show that the homologous repair machinery is required for producing the protective loops that characterize a mature functional telomere. They therefore propose a two-step model of telomere processing in which, rather than being shielded from being recognized as damage, the DNA damage machinery has an essential role.
Patrick Goymer
References
- Verdun, R. E. & Karlseder, J. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127, 709–720 (2006) | Article | PubMed |
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