TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs

Parnandi, Nishita; Rendo, Verónica; Cui, Gaofeng; Botuyan, Maria Victoria; Remišová, Michaela; Nguyen, Huy; Drané, Pascal; Beroukhim, Rameen; Altmeyer, Matthias; Mer, Georges; Chowdhury, Dipanjan

doi:10.1016/j.molcel.2021.03.039

Cited by 21 publications

(14 citation statements)

References 53 publications

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“…Wang et al (73) demonstrated that three loops (α1-β1 loop, N-terminus loop and β4-β5 loop) from TIRR interact with the 53BP1 Tudor domain and mask the methylated lysine-binding pocket in tandem Tudor domain. Additionally, TIRR inhibited the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2), which inhibited transcriptional activation of the p53 target genes (75). Overall, these studies elucidate the mechanisms by which TIRR recognizes the 53BP1 Tudor domain and functions as a cellular inhibitor of the histone methyl-lysine readers.…”

Section: Upstream Regulators Of 53bp1 In Nhej Repairmentioning

confidence: 80%

Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review)

Lei

Peng

et al. 2022

Int J Mol Med

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The repair of dNA double-strand breaks (dSBs) is crucial for the preservation of genomic integrity and the maintenance of cellular homeostasis. Non-homologous dNA end joining (NHEJ) is the predominant repair mechanism for any type of dNA dSB during the majority of the cell cycle. NHEJ defects regulate tumor sensitivity to ionizing radiation and anti-neoplastic agents, resulting in immunodeficiencies and developmental abnormalities in malignant cells. p53-binding protein 1 (53BP1) is a key mediator involved in dSB repair, which functions to maintain a balance in the repair pathway choices and in preserving genomic stability. 53BP1 promotes dSB repair via NHEJ and antagonizes dNA end overhang resection. At present, novel lines of evidence have revealed the molecular mechanisms underlying the recruitment of 53BP1 and dNA break-responsive effectors to dSB sites, and the promotion of NHEJ-mediated dSB repair via 53BP1, while preventing homologous recombination. In the present review article, recent advances made in the elucidation of the structural and functional characteristics of 53BP1, the mechanisms of 53BP1 recruitment and interaction with the reshaping of the chromatin architecture around dSB sites, the post-transcriptional modifications of 53BP1, and the up-and downstream pathways of 53BP1 are discussed. The present review article also focuses on the application perspectives, current challenges and future directions of 53BP1 research.

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Section: Upstream Regulators Of 53bp1 In Nhej Repairmentioning

confidence: 80%

Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review)

Lei

Peng

et al. 2022

Int J Mol Med

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“…Interactions between 53BP1 and TIRR, NuMA, or lamin B1 are severed after IR induced DNA damages ( 18 , 19 ). TIRR protein has been recently reported to be an important inhibitor of the 53BP1-P53 complex and therefore controls p53-mediated cell fate program ( 63 ). Recent studies indicated that 53BP1 nuclear compartments show features of liquid-liquid phase separation ( 64 , 65 ).…”

Section: Discussionmentioning

confidence: 99%

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

et al. 2021

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Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction is dissociated after DNA damage. Lamin B1 overexpression impedes 53BP1 recruitment to DNA damage sites and leads to a persistence of DNA damage, a defect in nonhomologous end joining and an increased sensitivity to DSBs. The identification of interactions domains between lamin B1 and 53BP1 allows us to demonstrate that the defect of 53BP1 recruitment and the DSB persistence upon lamin B1 overexpression are due to sequestration of 53BP1 by lamin B1. This study highlights lamin B1 as a factor controlling the recruitment of 53BP1 to DNA damage sites upon injury.

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“…Recent works [ 14 , 15 , 16 , 17 ] highlighted a fundamental role of 53BP1 in the p53 control of cell-fate programs.…”

Section: Introductionmentioning

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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TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs

Cited by 21 publications

References 53 publications

Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review)

Multifaceted regulation and functions of 53BP1 in NHEJ‑mediated DSB repair (Review)

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage

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

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