A role for the Rb family of proteins in controlling telomere length.
The molecular mechanisms of cellular mortality have recently begun to be unraveled. In particular, it has been discovered that cells that lack telomerase are subject to telomere attrition with each round of replication, eventually leading to loss of telomere capping function at chromosome ends. Critically short telomeres and telomeres lacking telomere-binding proteins lose their functionality and are metabolized as DNA breaks, thus generating chromosomal fusions. Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacity. In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization. Here, we report a connection between the members of the retinoblastoma family of proteins, Rb1 (retinoblastoma 1), Rbl1 (retinoblastoma-like 1) and Rbl2 (retinoblastoma-like 2), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in Rbl1, Rbl2 and Rb1 have markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length is not associated with increased telomerase activity. Notably, the abnormally elongated telomeres in doubly or triply deficient cells retain their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells.
García-Cao
Marta
M
Department of Immunology and Oncology, National Center of Biotechnology, E-28049 Madrid, Spain.
Gonzalo
Susana
S
Dean
Douglas
D
Blasco
María A
MA
D000818:Animals; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism / Q000502:physiology*; D050720:Retinoblastoma-Like Protein p107; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure*
D009687:Nuclear Proteins; C489485:Rbl1 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D004247:DNA; D019098:Telomerase