PLoS Genetics (Nov 2022)

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

  • 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

DOI
https://doi.org/10.1371/journal.pgen.1010506
Journal volume & issue
Vol. 18, no. 11
p. e1010506

Abstract

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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.