Telomere Dysfunction Results in Genomic Instability

Cytogenetic analysis by McClintock on breakage and fusion of maize chromosomes provided the first evidence that proper maintenance of telomeres is important for chromosomal integrity and genome stability. Dysfunctional telomeric ends are highly recombinogenic, leading to the improper chromosomal fusions, some of which may end up as dicentric chromosomes. During anaphase, dicentric chromosomes may be pulled to opposite ends of the cell, forming an anaphase bridge if the two kinetochores from the same chromatid are attached to the opposite spindle poles. Subsequent random chromosome breakage will generate broken chromosomes in the daughter cells, leading to the breakage-fusion-bridge (BFB) cycle proposed by McClintock. Since the break could occur anywhere along the anaphase bridge, this type of genomic instability may lead to loss of heterozygocity (LOH) in one daughter cell while the other daughter gains extra genetic information: regional chromosome amplification occurs if information from a homologous chromosome is gained or nonreciprocal translocations (NRTs) occur if information is from a different chromosome. Therefore, the occasional formation of dicentric chromosomes fueled by telomere dysfunction may trigger an endless chain of BFB events, constantly generating novel chromosomal variants with each cell division.

The importance of telomere length in regulating genome stability has been extended across many species. Fission yeast engineered without telomerase die after extensive passage, with rare survivors emerging with recombined (circularized)

chromosomes to eliminate the need for telomeres entirely (Nakamura et al. 1997) or activate the ALT pathway to regenerate functional telomeres (Lundblad and Blackburn 1993). Elevated genomic instability characterized by the formation of NRTs via the BFB cycle was observed in telomerase-null Sachromyces cerevi-siae possessing dysfunctional telomeres (Hackett et al. 2001). In late-generation mTerc-/- mice, chromosomes isolated from lymphocytes and embryonic fibrob-lasts exhibited p-arm-to-p-arm chromosomal fusions, a hallmark of telomere dysfunction (Blasco et al. 1997, Lee et al. 1998, Rudolph et al. 1999). Increased telomere loss leads to the formation of complex cytogenetic rearrangements, including dicentric chromosomes and the generation of NRTs (reviewed in Maser and DePinho 2002, Hande et al. 1999, Artandi et al. 2000, Chang et al. 2003). The decline in telomere length, rather than the absence of telomerase activity per se, appears to be the most important parameter dictating chromosomal integrity, since early-generation mTerc-/- mice, which still possess long telomeres, are cytogeneti-cally and biologically normal. These results further highlight the importance of tel-omerase in preserving genome stability by preventing telomere dysfunction, thus inhibiting the initiation of BFB cycles and abrogation of their adverse effects.

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