The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair

Moreno, Naike Salvador; Liu, Jing; Haas, Karen M.; Parker, Laurie L.; Chakraborty, Chaitali; Kron, Stephen J.; Hodges, Kurt; Miller, Lance D.; Langefeld, Carl; Robinson, Paul; Lelièvre, Sophie A.; Vidi, Pierre Alexandre

doi:10.1093/nar/gkz802

Cited by 13 publications

(15 citation statements)

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“…As USP28 and NuMA1 likely interact in mitotic cells and USP28 depletion did not have an impact on NuMA1 protein levels, our data suggest a new ubiquitin-dependent mechanism that might be involved in control of clustering of extra centrosomes. Interestingly, recent evidence suggests a function of NuMA1 also in cellular response to DNA damage (Moreno et al, 2019). Future research will show whether this novel function of NuMA1 also contributes to cellular response to tetraploidy.…”

Section: Discussionmentioning

confidence: 93%

USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling

Seget-Trzensiok¹,

Bernhard²,

Kuffer

et al. 2020

Preprint

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Tetraploidy is frequent in cancer and whole genome doubling shapes the evolution of cancer genomes, thereby driving the transformation, metastasis and drug resistance. Yet, human cells usually arrest when they become tetraploid due to p53 activation that leads to CDKN1A expression, cell cycle arrest, senescence or apoptosis. To uncover the barriers that block proliferation of tetraploids, we performed an RNAi mediated genome-wide screen in a human cancer cell line. We identified 140 genes whose depletion improved survival of tetraploids and characterized in depth two of them: SPINT2 and USP28. We show that SPINT2 is a general regulator of CDKN1A, regulating its transcription via histone acetylation. By mass spectrometry and immunoprecipitation, we show that USP28 interacts with NuMA1 and affects centrosome clustering. Moreover, tetraploid cells accumulate DNA damage and loss of USP28 reduces checkpoint activation. Our results indicate three aspects that contribute to survival of tetraploid cells: i) increased mitogenic signaling and reduced expression of cell cycle inhibitors, ii) the ability to establish functional bipolar spindle, and iii) reduced DNA damage signaling.

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Section: Discussionmentioning

confidence: 93%

USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling

Seget-Trzensiok¹,

Bernhard²,

Kuffer

et al. 2020

Preprint

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“…4F). NuMa1 was recently shown to control diffusion of 53BP1 (44). More specifically, NuMa1 was shown to reduce 53BP1 motility outside of DNA repair foci with no effect on total 53BP1 levels.…”

Section: Inhibition Of Tdo Resulted In Loss Of Sirtuin Signaling Andmentioning

confidence: 99%

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Reed

Maddukuri

Ketkar

et al. 2020

Preprint

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Aberrant expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy and immune response in gliomas in part through kynurenine (KYN)-mediated activation of the aryl hydrocarbon receptor (AhR). In the current study, we investigated the hypothesis that TDO activation in gliomas has a broad impact upon genome maintenance -promoting tolerance of replication stress (RS) and repair of DNA damage. We report that inhibition of TDO activity attenuated recovery from hydroxyurea (HU)-induced RS and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU), as fork progress was impeded when TDO-deficient glioma cells were treated with BCNU. Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to treatment with BCNU, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced -indicative of increased fork collapse. Restoration of KYN levels protected against some replication-associated effects of BCNU. Inhibition of TDO activity had a strong anti-proliferative effect on glioma-derived cells -enhancing the cytotoxic effects of BCNU. Analysis of results obtained using quantitative proteomics revealed TDOdependent changes in several signaling pathways -including down-regulation of DNA repair factors and sirtuin signaling. Consistent with these observations, inhibition of TDO diminished SIRT7 recruitment to chromatin, which increased histone H3K18 acetylation -a key mark involved in 53BP1 recruitment to sites of DNA damage. Cells lacking TDO activity exhibited defective recruitment of 53BP1 to gH2AX foci, which corresponded with delayed repair of BCNU-induced DNA breaks. Addition of exogenous KYN increased the rate of break repair. The discovery that TDO activity modulates sensitivity to DNA damage by fueling SIRT7/53BP1 localization to chromatin and repair of BCNU-induced DNA damage highlights the potential for tumor-specific metabolic changes to influence genome stability and may have implications for glioma biology and treatment strategies.

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“…A new role for NuMA was revealed related to diffusion regulation of P53-binding protein 1 (53BP1) which plays a prominent role in DNA repair. Higher NuMA mRNA levels were significantly linked to increased breast cancer patients survival even when specifically analyzed in basal-like tumors [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of the SPAG5 gene expression and amplification related to the NuMA mRNA levels in breast ductal carcinoma

Mohamadalizadeh-Hanjani

Shahbazi

Geranpayeh

2020

World J Surg Onc

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Background The cell proliferative markers are very important in breast cancer. Since SPAG5 and NuMA proteins play a significant role in the mitosis regulatory network and cell division, we aimed to study their mRNA levels as well as SPAG5 gene amplification correlated to clinicopathological status in ductal carcinoma of the breast. Methods SPAG5 and NuMA gene expressions were investigated in 40 breast cancer tissues and normal adjacent tissues via real-time PCR. PUM1 was selected as the reference gene. QMF PCR method was applied to study SPAG5 gene amplification and AGBL2, BOD1L, and POR were designated as internal control genes. Gene amplification was determined by calculating a dosage quotient for each DNA fragment. Results Increased SPAG5 mRNA expression was detected in breast cancer tissues ( p = 0.005) and related to tumor size. No significant difference was observed between NuMA gene expression level in tumor tissue and the normal adjacent tissue ( p = 0.56). However, we observed that NuMA expression was significantly increased in ER-positive tumor tissues. There was no clear correlation pattern between SPAG5 and NuMA mRNA levels ( r = 0.33). Seventeen percent of tissues showed complete amplification in SPAG5 gene fragments. Conclusion Our results were consistent with the previous publications regarding SPAG5 gene expression and amplification in breast cancer with an emphasis on the prominent role of this protein in tumor pathogenesis. Our results failed to yield any correlation between SPAG5 and NuMA mRNA levels which implies independence of these genes in breast cancer pathogenesis.

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The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair

Cited by 13 publications

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USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling

USP28 and SPINT2 mediate cell cycle arrest after whole genome doubling

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Investigation of the SPAG5 gene expression and amplification related to the NuMA mRNA levels in breast ductal carcinoma

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