In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 11 ( 2022-11-28), p. e1010506-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010506
DOI:
10.1371/journal.pgen.1010506.g001
DOI:
10.1371/journal.pgen.1010506.g002
DOI:
10.1371/journal.pgen.1010506.g003
DOI:
10.1371/journal.pgen.1010506.g004
DOI:
10.1371/journal.pgen.1010506.g005
DOI:
10.1371/journal.pgen.1010506.g006
DOI:
10.1371/journal.pgen.1010506.g007
DOI:
10.1371/journal.pgen.1010506.g008
DOI:
10.1371/journal.pgen.1010506.s001
DOI:
10.1371/journal.pgen.1010506.s002
DOI:
10.1371/journal.pgen.1010506.s003
DOI:
10.1371/journal.pgen.1010506.s004
DOI:
10.1371/journal.pgen.1010506.s005
DOI:
10.1371/journal.pgen.1010506.s006
DOI:
10.1371/journal.pgen.1010506.s007
DOI:
10.1371/journal.pgen.1010506.s008
DOI:
10.1371/journal.pgen.1010506.s009
DOI:
10.1371/journal.pgen.1010506.s010
DOI:
10.1371/journal.pgen.1010506.s011
DOI:
10.1371/journal.pgen.1010506.s012
DOI:
10.1371/journal.pgen.1010506.s013
DOI:
10.1371/journal.pgen.1010506.s014
DOI:
10.1371/journal.pgen.1010506.s015
DOI:
10.1371/journal.pgen.1010506.s016
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2186725-2
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