Cellular and chromosomal consequences of telomere dysfunction

Carol W. Greider, Margaret Strong, Ling-Yang Hao, Ling Qi, Mary Armanios, Arne IJpma, and Jennifer Hackett. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore MD 21205

Telomerase is required for the maintenance of telomere length. In the absence of telomerase telomeres shorten and cells undergo chromosomal rearrangments, cellular senescence or cell death, depending on the cell type. We are examining both the cellular response to short telomeres and the chromosomal consequence of loss of telomere function. Short dysfunctional telomeres signal a cellular response that is similar to the response to double stranded DNA breaks. The telomerase-null mouse shows progressive telomere shortening and increased germ cell apoptosis with each generation of breeding. The shortest telomere in the telomere length distribution signals a cellular response that can lead to apoptosis [1]. Consistent with short telomeres signaling a DNA damage type of response, we found phosphorylation of the histone variant H2AX at short telomeres in cells that lack telomerase [2]. Such phosphorylation of H2AX is found at sites of double stranded DNA breaks. Although ATM plays a role in the response to double strand DNA breaks, surprisingly, in the atm-/- mTR-/- double null mice, ATM is not required for apoptosis in response to short telomeres. In fact ATM plays a role in protecting short telomeres from being recognized as DNA damage [3].  In yeast, telomere shortening signals a G2/M cell cycle arrest that is similar to a Mec1 and Rad24 dependant DNA damage checkpoint response [4]. Those cells that do not arrest show an increased mutation rate due to chromosome rearrangements and reciprocal translocations [5]. Although chromosome end-to-end fusions are often seen in cells that lack telomere function, exonucleolytic end resection and the generation of single stranded DNA initiate the chromosomal instability in telomerase null yeast cells [6]. Thus the major molecular mechanism by which short telomeres trigger chromosome rearrangement is though non-reciprocal translocations not through cycles of breakage fusion and bridge formation.

1. Hemann, M.T., et al., The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell, 2001. 107: p. 67-77.
2. Hao, L.-Y. and C.W. Greider, Phosphorylation of H2AX at short telomeres in T cells and fibroblasts. submitted, 2003.
3. Qi, L., et al., Short telomeres and loss of ATM synergistically increase telomere dysfunction and suppress tumorigenesis. Cancer Research, 2003. in press.
4. IJpma, A. and C.W. Greider, Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. Molec Biol Cell, 2003. 14(3): p. 987-1001.
5. Hackett, J., D.M. Feldser, and C.W. Greider, Telomere dysfunction increases mutation rate and genomic instability. Cell, 2001. 106: p. 275-286.
6. Hackett, J.A. and C.W. Greider, End resection initiates genomic instability in the absence of telomerase. Mol Cell Biol, 2003. 23(23): p. 8450-61.