Abstract
Genetic instability is the driving force of the malignant progression of cancer cells. Recently, replication stress has attracted much attention as a source of genetic instability that gives rise to an accumulation of mutations during the lifespan of individuals. However, the molecular details of the process are not fully understood. Here, recent progress in understanding how genetic alterations accumulate at telomeres will be reviewed. In particular, two aspects of telomere replication will be discussed in this context, covering conventional semi-conservative replication, and DNA synthesis by telomerase plus the C-strand fill-in reactions. Although these processes are seemingly telomere-specific, I will emphasize the possibility that the molecular understanding of the telomere events may shed light on genetic instability at other genetic loci in general.
Highlights
Genetic instability is the driving force of the malignant progression of cancer cells
A protein complex called shelterin forms the constitutive telomere architecture that is required for vital telomere function.[5]. Shelterin consists of six proteins, TRF1, TRF2, TIN2, Rap1, TPP1 and POT1 (Fig. 2)
It was suggested that the replication fork progressed slowly at telomeres in HeLa cells when TRF1 or TRF2 was overexpressed.[7]. These results suggested that TRF1 and ⁄ or TRF2-bound telomere chromatin was a poor substrate for DNA replication
Summary
Graduate School of Biostudies, Kyoto University, Kyoto, Japan (Received December 27, 2012 ⁄ Revised March 16, 2013 ⁄ Accepted March 19, 2013 ⁄ Accepted manuscript online April 4, 2013 ⁄ Article first published online May 12, 2013). Two aspects of telomere replication will be discussed in this context, covering conventional semi-conservative replication, and DNA synthesis by telomerase plus the C-strand fill-in reactions. These processes are seemingly telomere-specific, I will emphasize the possibility that the molecular understanding of the telomere events may shed light on genetic instability at other genetic loci in general. The telomere is a chromosomal domain essential for the faithful maintenance of the genome It protects the end of a linear genomic DNA from illegitimate DNA repair reactions and prevents activation of the DNA damage checkpoint. I will describe the molecular mechanism that ensures telomere integrity in the face of replication stress
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