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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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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
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author 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
author_facet 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
author_sort Stock, Amanda J.
collection PubMed
description 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.
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spelling pubmed-97046292022-11-29 Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes 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 PLoS Genet Research Article 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. Public Library of Science 2022-11-28 /pmc/articles/PMC9704629/ /pubmed/36441670 http://dx.doi.org/10.1371/journal.pgen.1010506 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
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
Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title_full Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title_fullStr Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title_full_unstemmed Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title_short Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes
title_sort aberrant expression and localization of the rap1 shelterin protein contribute to age-related phenotypes
topic Research Article
url 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
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