First Author | Stock AJ | Year | 2022 |
Journal | PLoS Genet | Volume | 18 |
Issue | 11 | Pages | e1010506 |
PubMed ID | 36441670 | Mgi Jnum | J:332126 |
Mgi Id | MGI:7410307 | Doi | 10.1371/journal.pgen.1010506 |
Citation | Stock AJ, et al. (2022) Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes. PLoS Genet 18(11):e1010506 |
abstractText | Short telomeres induce a DNA damage response (DDR) that evokes apoptosis and senescence in human cells. An extant question is the contribution of telomere dysfunction-induced DDR to the phenotypes observed in aging and telomere biology disorders. One candidate is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knockin mouse carrying a mutated Rap1, which was incapable of binding telomeres and did not result in eroded telomeres or a DDR. Primary Rap1 knockin embryonic fibroblasts showed decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in human fibroblasts undergoing telomere erosion. Rap1 knockin mice were viable, but exhibited transcriptomic alterations, proinflammatory cytokine/chemokine signaling, reduced lifespan, and decreased healthspan with increased body weight/fasting blood glucose levels, spontaneous tumor incidence, and behavioral deficits. Taken together, our data present mechanisms distinct from telomere-induced DDR that underlie age-related phenotypes. |