Publication — IRIC

Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes.

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.

Date de publication
1er novembre 2022
Stock AJ, McDevitt RA, Puligilla C, Wang Y, Zhang Y, Wang K, Sun C, Becker KG, Lehrmann E, Wood WH, Gong Y, Aqdas M, Sung MH, Hoffmann V, Liu C, Gorospe M, Harrington L, Ferrucci L, Liu Y
Référence PubMed
PLoS Genet 2022;18(11):e1010506
ID PubMed
Laboratory of Genetics and Genomics, National Institute on Aging/National Institutes of Health, Baltimore, Maryland, United States of America.