ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition
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ABSTRACT:
SUBMITTER: Bakr A
PROVIDER: S-EPMC8599806 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.
2022-02-17 | PXD028946 | Pride
Project description:PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes varies widely in mCRPC and the impact of the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay. PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors olaparib and rucaparib across a panel of prostate cancer cell lines. These data support PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity and highlight the potential to use functional approaches to complement and extend findings from clinical trials of targeted agents.
| S-EPMC9242979 | biostudies-literature
Project description:PARP inhibitors (PARPi) have emerged as a promising targeted therapeutic intervention for metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi is limited to a subset of patients who harbor aberrations in the genes associated with the homologous recombination (HR) pathway. Here, we report that targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an oncogenic long noncoding RNA (lncRNA), contrives a BRCAness-like phenotype, and augments sensitivity to PARPi. Mechanistically, we show that MALAT1 silencing reprograms the homologous recombination (HR) transcriptome and makes prostate cancer cells more vulnerable to PARPi. Particularly, coinhibition of MALAT1 and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci, and reduces tumor burden in mice xenograft model. Moreover, we show that miR-421, a tumor suppressor miRNA, negatively regulates the expression of HR genes, while in aggressive prostate cancer cases, miR-421 is sequestered by MALAT1, leading to increased expression of HR genes. Conclusively, our findings suggest that MALAT1 ablation confers sensitivity to PARPi, thus highlighting an alternative therapeutic strategy for patients with castration-resistant prostate cancer (CRPC), irrespective of the alterations in HR genes.SignificancePARPi are clinically approved for patients with metastatic CRPC carrying mutations in HR genes, but are ineffective for HR-proficient prostate cancer. Herein, we show that oncogenic lncRNA, MALAT1 is frequently overexpressed in advanced stage prostate cancer and plays a crucial role in maintaining genomic integrity. Importantly, we propose a novel therapeutic strategy that emphasizes MALAT1 inhibition, leading to HR dysfunction in both HR-deficient and -proficient prostate cancer, consequently augmenting their susceptibility to PARPi.
| S-EPMC10561629 | biostudies-literature
Project description:Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.
| S-EPMC6830099 | biostudies-literature
Project description:Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in coordinating DNA repair and cell-cycle response following DNA damage, and ATM alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with BRCA1/2 alterations. However, the role of alterations in DDR genes beyond BRCA1/2 in mediating PARP inhibitor sensitivity is poorly understood. To define the role of ATM loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of ATM-deficient preclinical prostate cancer models and tested the impact of ATM loss on DNA repair function and therapeutic sensitivities. ATM loss altered DDR signaling, but did not directly impact homologous recombination function. Furthermore, ATM loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor ATM alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy. SIGNIFICANCE: ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.See related commentary by Setton and Powell, p. 2085.
| S-EPMC7272301 | biostudies-literature
Project description:PurposeWith the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In advanced prostate cancer patients with BRCA1/2 or ATM mutations, poly (ADP-ribose) polymerase inhibition (PARPi) causes an increased overall survival advantage compared with patients without these mutations. This review explores the advantages and limitations of PARPi treatment and its use beyond BRCA1/2-altered tumors. Furthermore, it discusses the benefits of current biomarkers and what role functional biomarkers and organoids may play in addressing the involvement of homologous recombination repair mutations in tumor development and progression.MethodsA systematic review was conducted in MEDLINE, National Library of Medicine, and ClinicalTrials.gov to identify studies published between January 1, 2016, and August 31, 2021. The search strategy incorporated terms for PARPi, BRCA, DNA damage, homologous recombination, organoids, patient-derived organoids, biomarker AND prostate cancer, breast cancer, ovarian cancer.ResultsA total of 261 records remained after duplicate removal, 69 of which were included in the qualitative synthesis.ConclusionTo improve the outcome of targeted therapy and increase sensitivity of tumor detection, patients should be repeatedly screened for DNA repair gene alterations and biomarkers. Future clinical studies should explore the use of PARPi beyond BRCA1/2 mutations and focus on finding new synthetically lethal interactions.
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Project description:In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.
| S-EPMC7155421 | biostudies-literature
Project description:Abstract Paediatric high grade glioma (pHGG) are defined by recurrent mutations in H3 histones, as well as frequent alterations in the SWI/SNF chromatin remodelling gene ATRX (α-thalassemia mental retardation X-linked), although the precise role of ATRX in tumorigenesis remains unclear. We sought to explore this using genomic analysis of patient samples, CRISPR-Cas9 engineered isogenic ATRX knockout (KO) cell lines and primary-patient-derived cultures. In combined retrospective and prospective cohorts of pHGG samples, we found ATRX mutations in 95/510 (18.6%) cases (27% hemispheric glioblastoma, 13% diffuse midline glioma), with the majority of truncating mutations found in the ADD domain, and missense mutations almost exclusively in the helicase domain. ATRX mutations commonly co-segregate with H3.3G34 and TP53 mutations, and define a subgroup of patients with a longer overall survival, though with a greater number of somatic mutations and copy number alterations than wild-type cases. CRISPR/Cas9-mediated ATRX KO targeting the ADD domain in TP53 mutant paediatric glioblastoma cells lead to loss of imprinting at the H19 locus in concert with upregulation of a pro-invasive transcriptional programme, though a slower rate of orthotopic tumour growth in vivo. ATRX deficient cells showed an abrogated DNA damage response, with prolonged accumulation of gH2AX foci after irradiation, and an increased dependency on PARP1 through persistent parylation and stalled replication forks. Screening ATRX-deficient isogenics and patient-derived cells against a library of >400 chemotherapeutics and small molecules identified a specific dependency for ATRX loss and sensitivity to distinct PARP inhibitor chemotypes, including catalytic inhibitors (olaparib, rucaparib), and PARP trappers (talazoparib). ATRX deficiency further conferred an enhanced radiosensitization of olaparib in vitro and a prolonged survival of mice treated with combined PARP inhibition and radiotherapy in vivo. These data suggest a synthetic lethality for PARP inhibitors in ATRX-deficient pHGG, and may represent a novel therapeutic strategy for these highly aggressive tumours.
| S-EPMC6217705 | biostudies-literature
Project description:Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of BRCA1 and RAD51, two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.
| S-EPMC5705017 | biostudies-literature
Project description:Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and represents a potential target for cancer therapies. ATRX is known to function as a histone chaperone that helps incorporate histone variant, H3.3, into the genome. Studies have implicated ATRX in key DNA damage response (DDR) pathways but a distinct role in DNA repair has yet to be fully elucidated. To further investigate the function of ATRX in the DDR, we created isogenic wild-type (WT) and ATRX knockout (KO) model cell lines using CRISPR-based gene targeting. These studies revealed that loss of ATRX confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors, which was linked to an increase in replication stress, as detected by increased activation of the ataxia telangiectasia and Rad3-related (ATR) signaling axis. ATRX mutations frequently co-occur with mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2), and the latter mutations also induce HR defects and PARP inhibitor sensitivity. We found that the magnitude of PARP inhibitor sensitivity was equal in the context of each mutation alone, although no further sensitization was observed in combination, suggesting an epistatic interaction. Finally, we observed enhanced synergistic tumor cell killing in ATRX KO cells with ATR and PARP inhibition, which is commonly seen in HR-defective cells. Taken together, these data reveal that ATRX may be used as a molecular marker for DDR defects and PARP inhibitor sensitivity, independent of IDH1/2 mutations. These data highlight the important role of common glioma-associated mutations in the regulation of DDR, and novel avenues for molecularly guided therapeutic intervention.
| S-EPMC8203843 | biostudies-literature