Loss of Rap1 Induces Telomere Recombination in the Absence of NHEJ or a DNA Damage Signal

The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Science (Impact Factor: 33.61). 03/2010; 327(5973):1657-61. DOI: 10.1126/science.1185100
Source: PubMed


Shelterin is an essential telomeric protein complex that prevents DNA damage signaling and DNA repair at mammalian chromosome ends. Here we report on the role of the TRF2-interacting factor Rap1, a conserved shelterin subunit of unknown function. We removed Rap1 from mouse telomeres either through gene deletion or by replacing TRF2 with a mutant that does not bind Rap1. Rap1 was dispensable for the essential functions of TRF2--repression of ATM kinase signaling and nonhomologous end joining (NHEJ)--and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair (HDR), which can alter telomere length. The data reveal that HDR at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within shelterin.

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    • "Contrastingly, the POT1-TPP1 complex positively regulates TL, likely due to the role of TPP1 in the recruitment of telomerase (Nandakumar et al., 2012; Wang et al., 2007). While a clear role of RAP1 has not been established, it has been shown to be involved in homologous recombination and inhibition of the DDR, and is recruited to telomeres via TRF2 (Sfeir et al., 2010). Deletion of RAP1 caused increased telomere damage and fragility (Martinez et al., 2010). "
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    ABSTRACT: Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are also associated with hyperactivity of the transcription factor NF-κB and overexpression of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ in circulating macrophages. Interestingly, telomerase, a reverse transcriptase that elongates telomeres, is involved in modulating NF-κB activity. Furthermore, inflammation and oxidative stress are implicated as pre-disease mechanisms for chronic diseases of ageing such as neurodegenerative diseases, cardiovascular disease, and cancer. To date, inflammation and telomere shortening have mostly been studied individually in terms of ageing and the associated disease phenotype. However, the interdependent nature of the two demands a more synergistic approach in understanding the ageing process itself and for developing new therapeutic approaches. In this review, we aim to summarize the intricate association between the various inflammatory molecules and telomeres that together contribute to the ageing process and related diseases.
    Full-text · Article · Nov 2015 · Ageing Research Reviews
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    • "Although loss of TRF2 or KU alone, or loss of both POT1a and POT1b together, exhibit only basal levels of T-SCEs (~1.5–3% of telomeres) in mouse embryonic fibroblasts (MEFs), T-SCEs are seen at approximately 10–15% of telomeres in MEFs lacking both TRF2 and KU, or in triple knockouts lacking POT1a, POT1b, and KU[49,50]. The role of TRF2 in suppressing T-SCEs may be mediated by its recruitment of RAP1, as KU-deficient MEFs expressing an allele of TRF2 that cannot bind to RAP1 also exhibit elevated T-SCE levels[51]. "

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    • "The only telomere deprotection phenotype in Rap1-deficient mouse cells is a propensity for telomere-telomere recombination when Ku70/80 are also absent (Sfeir et al., 2010). "
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    ABSTRACT: The conserved protein Rap1 functions at telomeres in fungi, protozoa, and vertebrates. Like yeast Rap1, human Rap1 has been implicated in telomere length regulation and repression of nonhomologous end-joining (NHEJ) at telomeres. However, mouse telomeres lacking Rap1 do not succumb to NHEJ. To determine the functions of human Rap1, we generated several transcription activator-like effector nuclease (TALEN)-mediated human cell lines lacking Rap1. Loss of Rap1 did not affect the other components of shelterin, the modification of telomeric histones, the subnuclear position of telomeres, or the 3' telomeric overhang. Telomeres lacking Rap1 did not show a DNA damage response, NHEJ, or consistent changes in their length, indicating that Rap1 does not have an important function in protection or length regulation of human telomeres. As human Rap1, like its mouse and unicellular orthologs, affects gene expression, we propose that the conservation of Rap1 reflects its role in transcriptional regulation rather than a function at telomeres. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Reports
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