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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-11-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010506 |
| _version_ | 1797973910884450304 |
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| author | Amanda J Stock Ross A McDevitt Chandrakala Puligilla Yajun Wang Yongqing Zhang Kun Wang Chongkui Sun Kevin G Becker Elin Lehrmann William H Wood Yi Gong Mohammad Aqdas Myong-Hee Sung Victoria Hoffmann Chengyu Liu Myriam Gorospe Lea Harrington Luigi Ferrucci Yie Liu |
| author_facet | Amanda J Stock Ross A McDevitt Chandrakala Puligilla Yajun Wang Yongqing Zhang Kun Wang Chongkui Sun Kevin G Becker Elin Lehrmann William H Wood Yi Gong Mohammad Aqdas Myong-Hee Sung Victoria Hoffmann Chengyu Liu Myriam Gorospe Lea Harrington Luigi Ferrucci Yie Liu |
| author_sort | Amanda J Stock |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T04:11:41Z |
| format | Article |
| id | doaj.art-42f878754db94ac392eb2d05bf6182d1 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-11T04:11:41Z |
| publishDate | 2022-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-42f878754db94ac392eb2d05bf6182d12023-01-01T05:32:04ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-11-011811e101050610.1371/journal.pgen.1010506Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes.Amanda J StockRoss A McDevittChandrakala PuligillaYajun WangYongqing ZhangKun WangChongkui SunKevin G BeckerElin LehrmannWilliam H WoodYi GongMohammad AqdasMyong-Hee SungVictoria HoffmannChengyu LiuMyriam GorospeLea HarringtonLuigi FerrucciYie LiuShort 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.https://doi.org/10.1371/journal.pgen.1010506 |
| spellingShingle | Amanda J Stock Ross A McDevitt Chandrakala Puligilla Yajun Wang Yongqing Zhang Kun Wang Chongkui Sun Kevin G Becker Elin Lehrmann William H Wood Yi Gong Mohammad Aqdas Myong-Hee Sung Victoria Hoffmann Chengyu Liu Myriam Gorospe Lea Harrington Luigi Ferrucci Yie Liu Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes. PLoS Genetics |
| 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 |
| url | https://doi.org/10.1371/journal.pgen.1010506 |
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