Aberrant expression and localization of the RAP1 shelterin protein contributes to age-related phenotypes [2017]

Short telomeres induce a DNA damage response (DDR) that evokes apoptosis or senescence in human cells. An extant question is the contribution of this DDR to the phenotypes observed in telomeropathies. One exemplar is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knock-in mouse containing a Rap1 variant unable to bind telomeres but which did not result in eroded telomeres or a DDR. Rap1 variant MEFs exhibited decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in aging human fibroblasts. Rap1 knock-in mice were viable, but exhibited transcriptional alterations, proinflammatory cytokine/chemokine signaling, decreased lifespans, increased body weight/fasting blood glucose levels, increased spontaneous tumor incidence, and behavioral deficits. Taken together, our data indicate that some of the underlying mechanisms that drive telomeropathies may arise from phenotypes distinct from a telomere-induced DDR. Gene expression profiles for wild-type (WT) and Rap1-variant mice (MUT) were assayed using Agilent gene expression microarrays for 2-5 month old male mice, examining four tissues (Brain, Heart, Liver, and Muscle), with N=3 per genotype/tissue group for total of 24 microarray samples.