TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis

2015-01-13

TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis
01-26-2014d1627

"C:\Users\kurtw_000\Box Sync\DocDR\2014\01-26-2014d1626\TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis.pdf"

Abstract
TRF1 is a component of the shelterin complex at mammalian telomeres; however, a role for TRF1 in telomere
biology in the context of the organism is unclear. In this study, we generated mice with transgenic TRF1
expression targeted to epithelial tissues (K5TRF1 mice). K5TRF1 mice have shorter telomeres in the epidermis
than wild-type controls do, and these are rescued in the absence of the XPF nuclease, indicating that TRF1 acts
as a negative regulator of telomere length by controlling XPF activity at telomeres, similar to what was
previously described for TRF2-overexpressing mice (K5TRF2 mice). K5TRF1 cells also show increased end-to-
end chromosomal fusions, multitelomeric signals, and increased telomere recombination, indicating an impact
of TRF1 on telomere integrity, again similar to the case in K5TRF2 cells. Intriguingly, K5TRF1 cells, but not
K5TRF2 cells, show increased mitotic spindle aberrations. TRF1 colocalizes with the spindle assembly check-
point proteins BubR1 and Mad2 at mouse telomeres, indicating a link between telomeres and the mitotic
spindle. Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo
by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic
spindle checkpoint.

notes and highlights

some techniques used
-real-time quantitative PCR
-Q-FISH
-culturing cells
-TRF analysis
-ChIP analysis
-RNA dot blot
-clonogenic assays
-TRAP assay to measure telomerase activity
-B1-SINE Cobra method to measure global DNA methylation
-cytogenic analysis

-mutant mouse strain K5TRF1

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