A role for p53 in telomere protection

Tutton, Stephen; Lieberman, Paul M.

doi:10.1080/23723556.2016.1143078

Cited by 13 publications

(11 citation statements)

References 9 publications

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“…Loss of function mutations in p53 permit the accumulation of critically short and uncapped telomeres and consequent chromosome instability observed in many p53-mutated cancers. In addition to this canonical pathway, we describe a reciprocal p53-telomere regulation axis mediated through the direct binding of p53 to sequence-specific sites in human and mouse subtelomeres [9, 15].…”

Section: Discussionmentioning

confidence: 99%

“…The chromosome regions adjacent to the telomere repeats are referred to as subtlomeres and can also contribute to telomeric chromatin and telomere repeat stability [14]. Subtelomeres can bind to sequence-specific factors and at least one third of human subtelomeres contain high-affinity, sequence-specific p53 binding sites within 10 kB of the telomere repeat track [9, 15]. Subtelomeric binding of p53 stimulates transcription of telomere repeat-encoded RNA (TERRA) and also induces histone acetylation throughout the subtelomeric and telomere repeat region in response to DNA damage signaling [9].…”

Section: Introductionmentioning

confidence: 99%

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Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

et al. 2019

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Subtelomeric transcription and chromatin can have a significant impact on telomere repeat maintenance and chromosome stability. We have previously found that tumor suppressor protein p53 (TP53) can bind to retrotransposon-like elements in a majority of human subtelomeres to regulate TERRA transcription and telomeric histone acetylation in response to DNA damage. TP53 also prevents the accumulation of γH2AX DNA-damage signaling at telomeres. We now show that the inherited TP53 polymorphism Pro47Ser (hereafter S47), which is enriched in populations of African descent, is associated with elevated marks of telomere dysfunction. We found that human and mouse cells carrying the S47 variant show increased γH2AX DNA-damage signals at telomeres, as well as reduced TERRA transcription and subtelomeric histone acetylation in response to DNA damage stress. Cell-lines containing inducible genes for P47 or S47 versions of p53, as well mouse embryo fibroblasts (MEFs) reconstituted with human p53, showed elevated telomere-induced DNA damage foci and metaphase telomere signal loss in cells with S47. Human lymphoblastoid cell lines (LCLs) derived from individuals homozygous for S47, show increased accumulation of subtelomeric γH2AX and unstable telomere repeats in response to DNA damage relative to age matched LCLs homozygous for P47. Furthermore, LCLs with S47 had reduced replicative lifespan. These studies indicate that the naturally occurring S47 variant of p53 can affect telomeric chromatin, telomere repeat stability, and replicative capacity. We discuss the potential evolutionary significance of the S47 variant to African populations with respect to telomere regulation and the implications for inherited health disparities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

et al. 2019

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“…Prior cell-based studies have shown that DNMT3A loss of function increases telomere length, 34 TET2 loss of function decreases telomere length; 35,36 and p53 (TP53) protects telomeres from DNA damage. 37 Thus, we estimated the effect size of each mutated gene on LTL (Fig. 2a, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Bidirectional Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of intermediate potential

Nakao¹,

Bick²,

Taub³

et al. 2021

Preprint

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Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

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“…Tutton and Lieberman (18) reported that p53 protein is an essential tumour suppressor that activates the various transcription genes involved in cell stress response. p53 direct binding at human sub-telomeres quadrates with activation of transcription and magnifies telomere stability when exists DNA damage (18). Consequently, telomerase inhibitors (or telomere shortening) are now being considered as potential anticancer drugs.…”

Section: Role Of P53 On Telomere Stabilitymentioning

confidence: 99%

Phenolic compounds, saponins and alkaloids on cancer progression: emphasis on p53 expression and telomere length

Vakili¹,

George²,

Ayatollahi

et al. 2020

Cell Mol Biol (Noisy-le-grand)

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Telomere length is correlated with cell proliferation, and cancer cells are characterized by an uncontrolled cell cycle. Being apoptosis one of the checks and balances incorporated into cells cycle, due to its characteristics, cancer cells are able to overcome this process. In particular, the tumour suppressor protein p53 loss or inactivation can lead to activation of telomerase enzyme, which can make cells unable to detect DNA damages that spurs apoptosis. Some bioactive compounds, in particular phenolic compounds, saponins and alkaloids have revealed good abilities to affect p53 expression and indirectly control the telomere length. In this sense, this review gives a key emphasis to the ability of these compounds in blocking cancer progression by acting on p53 expression and controlling telomere length. As main findings, phenolic compounds, saponins and alkaloids interfere with cancer progression by stimulating p53 expression, which can cause pro-apoptotic onset and restrict the anti-apoptotic activity, in addition to preventing telomerase enzyme activity.

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A role for p53 in telomere protection

Cited by 13 publications

References 9 publications

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

Elevated telomere dysfunction in cells containing the African-centric Pro47Ser cancer-risk variant of TP53

Bidirectional Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of intermediate potential

Phenolic compounds, saponins and alkaloids on cancer progression: emphasis on p53 expression and telomere length

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