A three-state model of telomere control over human proliferative boundaries

Abstract

Intrinsic limits on cellular proliferation in human somatic tissue serves as a tumor suppressor mechanism by restricting cell growth in aged cells with accrued pre-cancerous mutations. This is accompanied by the potential cost of restricting regenerative capacity and contributing to cellular and organismal aging. Emerging data support a model where telomere erosion controls proliferative boundaries through the progressive change of telomere structure from a protected state, through two distinct states of telomere deprotection. In this model telomeres facilitate a controlled permanent cell cycle arrest with a stable diploid genome during differentiation and may serve as an epigenetic sensor of general stress in DNA metabolism processes.

Figure 1

Graphical representation of human telomeres arranged in both linear and t-loop configuration. The shelterin components are expanded on the right and a micrograph of a metaphase chromosome with the DNA counterstained blue and the telomeres stained in green is shown on the left.

Figure 2

Graphical representation of closed-state, intermediate-state and uncapped-state human telomeres as predicted to occur during replicative aging or following experimental disruption of TRF2. The closed-state telomere is shown as a t-loop though this remains hypothetical. Intermediate-state telomeres are depicted as the result of excessive telomere shortening where steric constraints prevent formation of the protective closed state, and at an elongated telomere that has failed to form a closed-state due to partial depletion of TRF2. The activated DDR is indicated by a starburst. To the left is an example of a human metaphase chromosome with the DNA counterstained blue, the telomeres stained green, and γ-H2AX stained red. Chromatid-type metaphase-TIFs are evident on both arms of this chromosome. Uncapped-state telomeres are shown as the result of excessive shortening that has eroded all TRF2 binding sites, consistent with spontaneous fusions at crisis, and at elongated telomeres following experimental TRF2 deletion. The predicted fusion events are demonstrated in the middle. To the right are examples of fused chromosomes from human cells during lifespan extension that do not retain telomere repeats, and fused chromosomes in cells lacking TRF2 where telomeric repeats are evident within the dicentric chromosome.

Figure 3

Graphical representation of the DNA metabolic activities that occur normally at human telomeres in the context of the cell division cycle as described throughout the article text.