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Weinberg/Macmillan# s* v# T( ]) R. I& K
A: ]; d# g: ~/ a( q" j$ m) BCells with shortening telomeres hit two successive barriers: they first stop dividing as they become senescent, and later undergo a cell death process termed crisis. Although crisis may, as suggested by others, be controlled by overall telomere length, Sheila Stewart, Ittai Ben-Porath, Robert Weinberg (Whitehead Institute, Cambridge, MA), and colleagues now blame the onset of senescence on a particular structure at the end of telomeres.
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The important structure is a single-stranded overhang of G-rich residues at the 3' end. The group demonstrates that overhang length of several hundred bases is maintained over many generations of cell divisions, but drops to fewer than 100 residues at senescence. Telomerase increased overhang length, which may account for its ability to delay senescence. Various cellular stresses caused minor shortening of the overhang—cumulative stresses may therefore shorten it sufficiently to initiate senescence. Cells with inactivated p53 and Rb tumor suppressor pathways continued to divide despite loss of overhangs, suggesting that these cells are resistant to the putative growth inhibitory effects of overhang loss. Weinberg says the results indicate "the function of telomeres is unrelated to calculating the number of cell divisions. Instead, they represent signal transducing devices" that detect cellular stresses.The overhang is critical for forming the T-loop, which prevents end-to-end chromosome joining. Short overhangs may disrupt the T-loop, or another aspect of telomere structure, which may lead to release of a DNA damage signal that initiates p53 and Rb signaling.
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5 E$ F% U# {8 pStewart, S., et al. 2003. Nat. Genet. 10.1038/ng1127.(Overhang length drops at senescence (sen) |
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发表于 2009-3-6 00:36
发表于 2015-5-23 17:57
