TRIM29 is required for efficient recruitment of 53BP1 in response to DNA double‐strand breaks in vertebrate cells

Wikiniyadhanee, Rakkreat; Stitchantrakul, Wasana; Chitphuk, Sermsiri; Sura, Thanyachai; Dejsuphong, Donniphat

doi:10.1002/2211-5463.12954

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…Indeed, dROSHA knockdown and MRN complex inactivation (mirin treatment) increase the association of downstream HR factors, such as RAd51 to dNA ends and reduce NHEJ (125,126). Tripartite motif-containing protein 29 (TRIM29) is required for the efficient recruitment of 53BP1 to facilitate the NHEJ pathway and thereby suppress the HR pathway in response to dSB (127). The knockdown of histone lysine demethylase PHF2 inhibits the resolution of 53BP1 foci, the localization of c-terminal binding protein (ctBP)-interacting protein (ctIP) and subsequent NHEJ repair (128).…”

Section: Other Factors Involved In 53bp1 Recruitmentmentioning

confidence: 99%

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: Other Factors Involved In 53bp1 Recruitmentmentioning

confidence: 99%

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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“… 32 , 38 We inhibited 53BP1 nuclear foci formation by depleting RNF168 and confirmed that 53BP1 nuclear foci formation was required for ADR‐induced senescence. In addition to RNF168, several factors have been reported to regulate 53BP1 nuclear foci formation, 40 , 41 , 42 , 43 , 44 , 45 which might also regulate DNA damage‐induced senescence.…”

Section: Discussionmentioning

confidence: 99%

DNA damage‐induced cellular senescence is regulated by 53BP1 accumulation in the nuclear foci and phase separation

et al. 2023

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Cellular senescence is linked to a wide range of age‐related diseases and can be triggered by a variety of stresses, including DNA damage. A variety of genotoxic stressors, such as anti‐cancer drugs, cause DNA double‐strand breaks (DSBs), which trigger the accumulation of the tumour suppressor protein p53 in the nucleus. Cellular stresses stabilize and activate the p53 signalling pathway, which regulates various cellular processes, such as apoptosis, DNA repair, and senescence. Although p53 signalling is a well‐known tumour suppressor pathway, it remains unclear how it is regulated during cellular senescence. Here, we show that p53‐binding protein 1 (53BP1) accumulation in the nuclear foci is required for DNA damage‐induced cellular senescence via p53 activation. In human immortalized fibroblast, shRNA‐mediated 53BP1 depletion decreased not only the expression of p53‐target genes but also the cellular senescence induced by adriamycin treatment. Furthermore, we confirmed that DSBs trigger the hyperaccumulation of 53BP1 in the nuclear foci, which plays a key role in the regulation of cellular senescence. To prevent the accumulation of 53BP1 in the nuclear foci, we used phase separation inhibitors, and siRNA against RNF168, which accumulates at DSB loci and forms complexes with 53BP1. This blocks the formation of 53BP1 nuclear foci and DNA damage‐induced cellular senescence by activating the p53 signaling pathway. In conclusion, we demonstrated that increased accumulation of 53BP1 in the nuclear foci following DNA damage activates p53 and governs cellular senescence via a liquid–liquid phase separation mechanism.

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“…Cells were harvested onto glass slides using a Shandon Cytospin® 4 cytocentrifuge (Thermo Fisher Scientific, Inc.). A cell staining protocol for micronuclei and serine-139 phosphorylation of the histone variant H2AX (gH2AX) focus formation assays has been described previously [ 37 ]. Briefly, cells were subsequently fixed with 4% paraformaldehyde for 10 min, permeabilized with 0.5% Triton-X for 10 min, blocked with an Intercept® blocking buffer (cat.…”

Section: Methodsmentioning

confidence: 99%

ATR Inhibitor Synergizes PARP Inhibitor Cytotoxicity in Homologous Recombination Repair Deficiency TK6 Cell Lines

Wikiniyadhanee

Stitchantrakul

Chitphuk

et al. 2023

BioMed Research International

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The inhibition of poly(ADP-ribose) polymerases (PARPs) and ataxia telangiectasia and Rad3-related (ATR) would be an alternative approach for cancer treatments. The aim of this study is to investigate the synergy of the different combinations of PARP inhibitors (olaparib, talazoparib, or veliparib) and ATR inhibitor AZD6738. A drug combinational synergy screen that combines olaparib, talazoparib, or veliparib with AZD6738 was performed to identify the synergistic interaction, and the combination index was calculated to verify synergy. TK6 isogenic cell lines with defects in different DNA repair genes were used as a model. Cell cycle analysis, micronucleus induction, and focus formation assays of serine-139 phosphorylation of the histone variant H2AX demonstrated that AZD6738 diminished G2/M checkpoint activation induced by PARP inhibitors and allowed DNA damage-containing cells to continue dividing, leading to greater increases in micronuclei as well as double-strand DNA breaks in mitotic cells. We also found that AZD6738 was likely to potentiate cytotoxicity of PARP inhibitors in homologous recombination repair deficiency cell lines. AZD6738 sensitized more genotypes of DNA repair-deficient cell lines to talazoparib than to olaparib and veliparib, respectively. The combinational approach of PARP and ATR inhibition to enhance response to PARP inhibitors could expand the utility of PARP inhibitors to cancer patients without BRCA1/2 mutations.

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TRIM29 is required for efficient recruitment of 53BP1 in response to DNA double‐strand breaks in vertebrate cells

Cited by 5 publications

References 54 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)

DNA damage‐induced cellular senescence is regulated by 53BP1 accumulation in the nuclear foci and phase separation

ATR Inhibitor Synergizes PARP Inhibitor Cytotoxicity in Homologous Recombination Repair Deficiency TK6 Cell Lines

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