Subtelomeric p53 binding prevents accumulation of
            <scp>DNA</scp>
            damage at human telomeres

Tutton, Stephen; Azzam, Greggory A; Stong, Nicholas; Vladimirova, Olga; Wiedmer, Andreas; Monteith, Jessica A.; Beishline, Kate; Wang, Zhuo; Deng, Zhong; Riethman, Harold; McMahon, Steven B.; Murphy, Maureen E.; Lieberman, Paul M.

doi:10.15252/embj.201490880

Cited by 53 publications

(63 citation statements)

References 59 publications

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“…These fusions were most abundant in the TP53 −/− samples, in line with their raised inter-chromosomal fusion frequencies (Supplemental Fig. 1C) and further evidencing the significant genomic instability resulting from the loss of this mitotic checkpoint and subtelomeric protection (Tutton et al 2015). The absence of functional LIG3 or LIG4 did not significantly reduce the incidence of 17p intra-chromosomal fusion events detected, and importantly, the intra-chromosomal fusion frequency in the LIG3…”

Section: Intra-chromosomal Fusions Exhibit Asymmetrical Processingsupporting

confidence: 61%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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Telomeres shorten with each cell division and can ultimately become substrates for nonhomologous end-joining repair, leading to large-scale genomic rearrangements of the kind frequently observed in human cancers. We have characterized more than 1400 telomere fusion events at the single-molecule level, using a combination of high-throughput sequence analysis together with experimentally induced telomeric double-stranded DNA breaks. We show that a single chromosomal dysfunctional telomere can fuse with diverse nontelomeric genomic loci, even in the presence of an otherwise stable genome, and that fusion predominates in coding regions. Fusion frequency was markedly increased in the absence of TP53 checkpoint control and significantly modulated by the cellular capacity for classical, versus alternative, nonhomologous end joining (NHEJ). We observed a striking reduction in inter-chromosomal fusion events in cells lacking DNA ligase 4, in contrast to a remarkably consistent profile of intra-chromosomal fusion in the context of multiple genetic knockouts, including DNA ligase 3 and 4 doubleknockouts. We reveal distinct mutational signatures associated with classical NHEJ-mediated inter-chromosomal, as opposed to alternative NHEJ-mediated intra-chromosomal, telomere fusions and evidence for an unanticipated sufficiency of DNA ligase 1 for these intra-chromosomal events. Our findings have implications for mechanisms driving cancer genome evolution.

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Section: Intra-chromosomal Fusions Exhibit Asymmetrical Processingsupporting

confidence: 61%

Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

et al. 2016

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“…Genome-wide studies show that p53 binds to many loci in the genome, including sites not associated with transcriptional control [75]. Recently, the prevention of accumulation of DNA damage by p53 binding to subtelomeric regions has been described [76]. Walter et al showed that p53 induces local distortions in mismatched trinucleotide repeats and suggested that p53 may be involved in the maintenance of CTG.CAG tract stability [12, 30, 33].…”

Section: Discussionmentioning

confidence: 99%

p53 Specifically Binds Triplex DNA In Vitro and in Cells

et al. 2016

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Triplex DNA is implicated in a wide range of biological activities, including regulation of gene expression and genomic instability leading to cancer. The tumor suppressor p53 is a central regulator of cell fate in response to different type of insults. Sequence and structure specific modes of DNA recognition are core attributes of the p53 protein. The focus of this work is the structure-specific binding of p53 to DNA containing triplex-forming sequences in vitro and in cells and the effect on p53-driven transcription. This is the first DNA binding study of full-length p53 and its deletion variants to both intermolecular and intramolecular T.A.T triplexes. We demonstrate that the interaction of p53 with intermolecular T.A.T triplex is comparable to the recognition of CTG-hairpin non-B DNA structure. Using deletion mutants we determined the C-terminal DNA binding domain of p53 to be crucial for triplex recognition. Furthermore, strong p53 recognition of intramolecular T.A.T triplexes (H-DNA), stabilized by negative superhelicity in plasmid DNA, was detected by competition and immunoprecipitation experiments, and visualized by AFM. Moreover, chromatin immunoprecipitation revealed p53 binding T.A.T forming sequence in vivo. Enhanced reporter transactivation by p53 on insertion of triplex forming sequence into plasmid with p53 consensus sequence was observed by luciferase reporter assays. In-silico scan of human regulatory regions for the simultaneous presence of both consensus sequence and T.A.T motifs identified a set of candidate p53 target genes and p53-dependent activation of several of them (ABCG5, ENOX1, INSR, MCC, NFAT5) was confirmed by RT-qPCR. Our results show that T.A.T triplex comprises a new class of p53 binding sites targeted by p53 in a DNA structure-dependent mode in vitro and in cells. The contribution of p53 DNA structure-dependent binding to the regulation of transcription is discussed.

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“…29 Numerous studies showed that telomere dysfunction induces changes in cellular TERRA levels. 10,30,31 Depletion of TRF2 resulted in up-regulation of TERRA.…”

Section: Cfterra Biogenesismentioning

confidence: 99%