TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling

Sivakumar, Sushama; Qi, Shu-Tao; Cheng, Ningyan; Sathe, Adwait Amod; Kanchwala, Mohammed; Kumar, Ashwani; Evers, B. Mark; Xing, Chao; Yu, Hongtao

doi:10.1016/j.celrep.2022.110395

Cited by 19 publications

(19 citation statements)

References 73 publications

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“…In mouse embryonic stem cells (mESCs) the situation is different, since p53 can transactivate its target genes efficiently, resulting in a relatively low level of mutations due to their more robust repair capacity and/or elimination of genomically unstable cells by p53-induced apoptosis [ 48 ]. Furthermore, p53 might promote lineage commitment, as TP53−/− hESCs fail to differentiate into neural progenitor cells [ 49 ]. In any case, the role of p53 in regulating cell death during the organismal lifetime is crucial, keeping the balance between cell proliferation, DNA repair, and genome stability.…”

Section: Introductionmentioning

confidence: 99%

p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways

2022

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Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction of p53, there is no sign of any “mid-life crisis” in this rapidly advancing area of biomedicine. Firmly established as the hub of cellular stress responses and tumor suppressor targeted in most malignancies, p53’s many talents continue to surprise us, providing not only fresh insights into cell and organismal biology, but also new avenues to cancer treatment. Among the most fruitful lines of p53 research in recent years have been the discoveries revealing the multifaceted roles of p53-centered pathways in the fundamental processes of DNA replication and ribosome biogenesis (RiBi), along with cellular responses to replication and RiBi stresses, two intertwined areas of cell (patho)physiology that we discuss in this review. Here, we first provide concise introductory notes on the canonical roles of p53, the key interacting proteins, downstream targets and post-translational modifications involved in p53 regulation. We then highlight the emerging involvement of p53 as a key component of the DNA replication Fork Speed Regulatory Network and the mechanistic links of p53 with cellular checkpoint responses to replication stress (RS), the driving force of cancer-associated genomic instability. Next, the tantalizing, yet still rather foggy functional crosstalk between replication and RiBi (nucleolar) stresses is considered, followed by the more defined involvement of p53-mediated monitoring of the multistep process of RiBi, including the latest updates on the RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway and its involvement in tumorigenesis. The diverse defects of RiBi and IRBC that predispose and/or contribute to severe human pathologies including developmental syndromes and cancer are then outlined, along with examples of promising small-molecule-based strategies to therapeutically target the RS- and particularly RiBi- stress-tolerance mechanisms to which cancer cells are addicted due to their aberrant DNA replication, repair, and proteo-synthesis demands.

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Section: Introductionmentioning

confidence: 99%

p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways

2022

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“…Other recent studies suggest divergent roles for p53 in stem cell fate decisions during human pluripotent stem cell-based neurogenesis. Impaired neurogenesis is observed from p53 knockout (p53 −/− ) human embryonic stem cells (hESCs) and from p53KD hiPSCs 85 , 86 . Disorganized neuroepithelial rosettes were observed in neurodifferentiated p53 −/− hESCs 86 , and likewise limited neurogenesis was observed in p53 KD hiPSC-derived brain organoids 85 .…”

Section: Discussionmentioning

confidence: 99%

“…Impaired neurogenesis is observed from p53 knockout (p53 −/− ) human embryonic stem cells (hESCs) and from p53KD hiPSCs 85 , 86 . Disorganized neuroepithelial rosettes were observed in neurodifferentiated p53 −/− hESCs 86 , and likewise limited neurogenesis was observed in p53 KD hiPSC-derived brain organoids 85 . By contrast, exacerbated neurogenesis was observed when Marin Novarro, et al .…”

Section: Discussionmentioning

confidence: 99%

Transcription-associated DNA DSBs activate p53 during hiPSC-based neurogenesis

Michel

Young

Atkin

et al. 2022

Sci Rep

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Neurons are overproduced during cerebral cortical development. Neural progenitor cells (NPCs) divide rapidly and incur frequent DNA double-strand breaks (DSBs) throughout cortical neurogenesis. Although half of the neurons born during neurodevelopment die, many neurons with inaccurate DNA repair survive leading to brain somatic mosaicism. Recurrent DNA DSBs during neurodevelopment are associated with both gene expression level and gene length. We used imaging flow cytometry and a genome-wide DNA DSB capture approach to quantify and map DNA DSBs during human induced pluripotent stem cell (hiPSC)-based neurogenesis. Reduced p53 signaling was brought about by knockdown (p53KD); p53KD led to elevated DNA DSB burden in neurons that was associated with gene expression level but not gene length in neural progenitor cells (NPCs). Furthermore, DNA DSBs incurred from transcriptional, but not replicative, stress lead to p53 activation in neurotypical NPCs. In p53KD NPCs, DNA DSBs accumulate at transcription start sites of genes that are associated with neurological and psychiatric disorders. These findings add to a growing understanding of how neuronal genome dynamics are engaged by high transcriptional or replicative burden during neurodevelopment.

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“…This screening protocol can be adapted with other endpoint reporters for the identification of genes involved in the commitment of hESCs to other cell lineages. For complete details on the use and execution of this protocol, please refer to Sivakumar et al. (2022) .…”

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confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Sivakumar et al. (2022) .…”

mentioning

confidence: 99%