Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity

Wang, Yu‐Hsiu; Ho, Teck-Hua; Hariharan, Anushya; Goh, Hui Chin; Wong, Yao Liang; Verkaik, Nicole S.; Lee, May Yin; Tam, Wai Leong; Gent, Dik C. van; Venkitaraman, Ashok R.; Sheetz, Michael P.; Lane, David P.

doi:10.1073/pnas.2113233119

Cited by 53 publications

(67 citation statements)

References 70 publications

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“…Besides showing an alternative function for the 53BP1 DDR protein in helping the p53 action to regulate cell fate, the results evidenced a putative participation of the same p53 molecule in the recognition and repair of DD. A very recent paper [ 43 ] demonstrated the recruitment of p53 into γH2A.X foci for a transcription-independent function in an osteosarcoma cell model (U2OS). Our data confirm a potential direct involvement of the guardian of the genome in the DDR in a non-transformed cell model, thus including p53 in the targets worthy of a more detailed analysis for characterizing the cell response to a different type of radiation.…”

Section: Discussionmentioning

confidence: 99%

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

Furia

Pelicci²,

Scanarini³

et al. 2022

IJMS

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53BP1 protein has been isolated in-vitro as a putative p53 interactor. From the discovery of its engagement in the DNA-Damage Response (DDR), its role in sustaining the activity of the p53-regulated transcriptional program has been frequently under-evaluated, even in the case of a specific response to numerous DNA Double-Strand Breaks (DSBs), i.e., exposure to ionizing radiation. The localization of 53BP1 protein constitutes a key to decipher the network of activities exerted in response to stress. We present here an automated-microscopy for image cytometry protocol to analyze the evolution of the DDR, and to demonstrate how 53BP1 moved from damaged sites, where the well-known interaction with the DSB marker γH2A.X takes place, to nucleoplasm, interacting with p53, and enhancing the transcriptional regulation of the guardian of the genome protein. Molecular interactions have been quantitatively described and spatiotemporally localized at the highest spatial resolution by a simultaneous analysis of the impairment of the cell-cycle progression. Thanks to the high statistical sampling of the presented protocol, we provide a detailed quantitative description of the molecular events following the DSBs formation. Single-Molecule Localization Microscopy (SMLM) Analysis finally confirmed the p53–53BP1 interaction on the tens of nanometers scale during the distinct phases of the response.

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Section: Discussionmentioning

confidence: 99%

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

Furia

Pelicci²,

Scanarini³

et al. 2022

IJMS

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show abstract

“…In this study, however, the parental p21 +/+ cells did not express detectable amounts of p21 because of p53 deficiency, i.e., a genetic background known to affect NER efficiency [45][46][47]. Therefore, the evidence that DLD1/p21 −/− cells repaired UVB-induced lesions more efficiently than parental cells should be analyzed in the context of p53 and NER deficiency [47].…”

Section: Nucleotide Excision Repair (Ner)mentioning

confidence: 96%

“…It is worth considering that the lack of differences in DNA repair efficiency does not mean that p21 is an inhibitor, as it was implied by another study in which TCR efficiency in DLD1 parental cells was compared with a cell clone carrying an ablation of the p21 gene (DLD1/p21 −/− ) [20]. In this study, however, the parental p21 +/+ cells did not express detectable amounts of p21 because of p53 deficiency, i.e., a genetic background known to affect NER efficiency [45][46][47]. Therefore, the evidence that DLD1/p21 −/− cells repaired UVB-induced lesions more efficiently than parental cells should be analyzed in the context of p53 and NER deficiency [47].…”

Section: Nucleotide Excision Repair (Ner)mentioning

confidence: 99%

Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability

Ticli

Cazzalini

Stivala

et al. 2022

IJMS

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The p21CDKN1A protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.

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“…The TSS has previously been shown to have enriched DSB density compared to other genomic regions 46 , 59 – 61 . Elevated DNA DSB levels in p53 KD could be an indirect consequence of diminished p53-dependent transcriptional activation 88 , or these could arise as a direct consequence of impaired p53 recruitment to sites of DNA damage 89 . Further investigation is required to determine if elevated TSS-associated DNA DSBs are a direct or indirect consequence of p53 KD .…”

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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Rapid recruitment of p53 to DNA damage sites directs DNA repair choice and integrity

Cited by 53 publications

References 70 publications

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

From Double-Strand Break Recognition to Cell-Cycle Checkpoint Activation: High Content and Resolution Image Cytometry Unmasks 53BP1 Multiple Roles in DNA Damage Response and p53 Action

Revisiting the Function of p21CDKN1A in DNA Repair: The Influence of Protein Interactions and Stability

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

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