2026-06-14T06:44:19Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/85362024-11-29T18:31:40Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Martínez, Paula
author
Gómez-López, Gonzalo
author
Pisano, David G
author
Flores, Juana M
author
Blasco, MA
funder
Ministerio de Ciencia e Innovación (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Botín Foundation
2019-10-30T11:09:29Z
2019-10-30T11:09:29Z
2016-12
Aging Cell. 2016 Dec;15(6):1113-1125.
10.1111/acel.12517
1474-9726
14749718
Aging cell
27586969
http://hdl.handle.net/20.500.12105/8536
RAP1 is one of the components of shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere length maintenance and protection has remained elusive. RAP1 also binds subtelomeric repeats and along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres, and its deficiency causes a premature aging in humans and mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact on mouse survival, mice lacking both RAP1 and telomerase show a progressively decreased survival with increasing mouse generations compared to telomerase single mutants. Telomere shortening is more pronounced in Rap1-/- Terc-/- doubly deficient mice than in the single-mutant Terc-/- counterparts, leading to an earlier onset of telomere-induced DNA damage and degenerative pathologies. Telomerase deficiency abolishes obesity and liver steatohepatitis provoked by RAP1 deficiency. Using genomewide ChIP sequencing, we find that progressive telomere shortening owing to telomerase deficiency leads to re-localization of RAP1 from telomeres and subtelomeric regions to extratelomeric sites in a genomewide manner. These findings suggest that although in the presence of sufficient telomere reserve RAP1 is not a key factor for telomere maintenance and protection, it plays a crucial role in the context of telomerase deficiency, thus in agreement with its evolutionary conservation as a telomere component from yeast to humans.
eng
RAP1
Premature aging
Shelterins
Telomerase
Telomeres
A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere maintenance
journal article
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