NASP modulates histone turnover to drive PARP inhibitor resistance
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ABSTRACT:
PROVIDER: PRJEB86492 | ENA |
REPOSITORIES: ENA
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Project description:NASP modulates histone turnover to drive PARP inhibitor resistance
| PRJNA1244778 | ENA
Project description:NASP modulates histone turnover to drive PARP inhibitor resistance (Repli-Atac data)
| PRJEB90052 | ENA
Project description:PARP inhibitors (PARPi) present a remarkable advance in the treatment of patients with homologous recombination (HR)-deficient tumors but resistance remains a challenge1-5. While most research has focused on the downstream consequences of PARPi exposure to tackle resistance, the immediate impact of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here, we show that PARP inhibition induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant cancer cells, which are addicted to histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. NASP loss renders tumor cells hypersensitive to PARPi treatment in vitro and in vivo, impairs replication fork progression and elevates levels of replication-associated DNA damage. Moreover, NASP acts together with the INO80 complex and the chaperoning activity of PARP1 to ensure efficient histone turnover and prevent the accumulation of lethal DNA damage following PARPi exposure. Collectively, our work reports on histone eviction as an immediate cellular response to PARPi treatment and provides a promising avenue for targeting histone supply pathways to overcome PARPi resistance.
2025-07-29 | GSE293482 | GEO
Project description:PARP inhibitors (PARPi) present a remarkable advance in the treatment of patients with homologous recombination (HR)-deficient tumors1-3, however resistance remains a challenge due to genomic instability4,5. While most research has focused on the downstream consequences of PARPi exposure to tackle resistance, the immediate impact of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here, we show that PARP inhibition induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant cancer cells, which are addicted to histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. NASP loss renders tumor cells hypersensitive to PARPi treatment in vitro and in vivo, impairs replication fork progression and elevates levels of replication-associated DNA damage. Moreover, NASP acts together with the INO80 complex and the chaperoning activity of PARP1 to ensure efficient histone turnover and prevent the accumulation of lethal DNA damage following PARPi exposure. Collectively, our work reports on histone eviction as an immediate cellular response to PARPi treatment and provides a promising avenue for targeting histone supply pathways to overcome PARPi resistance.
2025-07-29 | PXD061071 | Pride
Project description:NF-kB regulator Bcl3 modulates bone density and turnover
| PRJNA515412 | ENA
Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells
2017-09-02 | GSE86394 | GEO
Project description:PARP inhibition and the effect on Arabidopsis thaliana high light tolerance
2012-05-01 | E-MTAB-896 | biostudies-arrayexpress
Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.
2013-12-31 | E-GEOD-43981 | biostudies-arrayexpress
Project description:We found that multilayered phosphorylation of human Tob2 modulates its PABP-binding ability to change global deadenylation and mRNA turnover, which in turn reprograms transcriptome to influence cell proliferation.
2020-08-26 | GSE149684 | GEO
Project description:We found that multilayered phosphorylation of human Tob2 modulates its PABP-binding ability to change global deadenylation and mRNA turnover, which in turn reprograms transcriptome to influence cell proliferation.
2020-08-26 | GSE137170 | GEO