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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...

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Detalles Bibliográficos
Autores principales: Stock, Amanda J., McDevitt, Ross A., Puligilla, Chandrakala, Wang, Yajun, Zhang, Yongqing, Wang, Kun, Sun, Chongkui, Becker, Kevin G., Lehrmann, Elin, Wood, William H., Gong, Yi, Aqdas, Mohammad, Sung, Myong-Hee, Hoffmann, Victoria, Liu, Chengyu, Gorospe, Myriam, Harrington, Lea, Ferrucci, Luigi, Liu, Yie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9704629/
https://www.ncbi.nlm.nih.gov/pubmed/36441670
http://dx.doi.org/10.1371/journal.pgen.1010506
Descripción
Sumario: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.