p53 directly represses human LINE1 transposons

Tiwari, Bhavana; Jones, Amanda E.; Caillet, Candace J.; Das, Simanti; Royer, Stephanie; Abrams, John

doi:10.1101/gad.343186.120

Cited by 65 publications

(73 citation statements)

References 70 publications

(95 reference statements)

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“…3a, S4b, d). Expression analysis using LINE-1 specific primers 33,34 showed a ~3-4-fold up-regulation of LINE-1 in Calu3 cells when infected by SARS-CoV-2 ( Fig. 3c).…”

Section: Human Endogenous Line-1 Expression Induced By Sars-cov-2 Infmentioning

confidence: 93%

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Zhang

Richards

Khalil

et al. 2020

Preprint

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SummaryProlonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious1–14. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

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“…3a, S4b, d). Expression analysis using LINE-1 specific primers 33,34 showed a ~3-4-fold up-regulation of LINE-1 in Calu3 cells when infected by SARS-CoV-2 ( Fig. 3c).…”

Section: Human Endogenous Line-1 Expression Induced By Sars-cov-2 Infmentioning

confidence: 93%

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Zhang

Richards

Khalil

et al. 2020

Preprint

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“…p53 binding sites occur in Alu elements and other retrotransposons through deamination of a methylated CpG site 47,48 . p53 can repress transposons through direct binding at these sites 49 . Since p63 and p73 share similar binding sites as p53, it is possible that in mammary epithelial cells, these sites are repurposed as regulatory elements through p63 binding.…”

Section: Aging-associated Dna Methylation Changes Occur At Lineage-specific Transcription Factor Binding Sitesmentioning

confidence: 99%

Normal mammary epithelia accumulate DNA methylation changes with age that are consistent with breast cancer methylomes

Senapati

Miyano

Sayaman

et al. 2020

Preprint

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The aging process is characterized by an accumulation of cellular damage, including alterations to the epigenome. While it is clear that DNA methylation patterns change with age, the mechanisms behind these epigenomic alterations - and their functional consequences - have remained unclear. One of the primary roles of DNA methylation in mammalian genomes is in the repression of retrotransposons. Many of these repetitive elements contain regulatory sequences, and loss of repression can lead to aberrant transcriptional regulation. Aging-associated DNA methylation loss at transposable elements (TEs), therefore, has the potential to rewire gene expression networks to be favorable for pathologies, including age-related diseases such as cancer. However, the extent of loss of epigenetic silencing at transposable elements during aging and the functional consequences of this have remained unclear. Luminal epithelial cells in the breast tissue are a key cell lineage implicated in age-related luminal breast cancers. We report here that aging leads to distinct DNA methylation patterns at tissue-specific regulatory elements and TEs in luminal epithelial cells. DNA methylation changes at regulatory elements are driven by altered activity of lineage-specific transcription factors such as ELF5 and TP63. However, transposable elements, especially recently evolved TEs, exhibit stochastic loss of methylation and increased methylation entropy with age. TEs that lose methylation with age regulate known breast cancer genes and are associated with elevated breast cancer risk. Altogether, our results indicate that aging leads to DNA methylation loss at evolutionarily young TEs that can impact gene networks important for age-related breast cancers.

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“…Importantly, efforts to comprehensively map p53REs may be encumbered by their frequent occurrence in respective, often methylated regions (which can be hard to map genomically with short read technologies) of the genome driven by proliferation of LINE elements [40]. The emerging importance of p53 and such elements in repressing retrotransposons during development and the potential vulnerability this imposes in p53 deficient cancers requires further study of the non-canonical role of p53 binding to these "dark" regions of the genome [41][42][43].…”

Section: P53-a Tumour Suppressive Transcription Factormentioning

confidence: 99%

Dying to Survive—The p53 Paradox

Lees

Sessler

McDade

2021

Cancers

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The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.

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p53 directly represses human LINE1 transposons

Cited by 65 publications

References 70 publications

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Normal mammary epithelia accumulate DNA methylation changes with age that are consistent with breast cancer methylomes

Dying to Survive—The p53 Paradox

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