ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer

Abstract Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that BRCA1 is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote BRCA1 transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces BRCA1 promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors, ZC3H18 and E2F4 mRNA levels are positively correlated with BRCA1 mRNA levels, further supporting ZC3H18 role in regulating BRCA1. Given that ZC3H18 lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that ZC3H18 copy number losses could contribute to HR defects in HGSOC.

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Capitalizing on synthetic lethality in homologous recombination-deficient high-grade serous ovarian cancers with a novel ATR inhibitor

Gynecologic Oncology ◽

10.1016/j.ygyno.2016.04.489 ◽

2016 ◽

Vol 141 ◽

pp. 189-190

Author(s):

E. George ◽

H. Kim ◽

R. Ragland ◽

E. Brown ◽

L. Butler ◽

...

Keyword(s):

Homologous Recombination ◽

Synthetic Lethality ◽

High Grade ◽

Ovarian Cancers

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Abstract 435: Cell-free circulating tumor DNA (ctDNA) detects somatic copy number loss in homologous recombination repair genes

10.1158/1538-7445.sabcs18-435 ◽

2019 ◽

Author(s):

Catalin Barbacioru ◽

Victoria M. Raymond ◽

Marcin Sikora ◽

Elena Helman ◽

Sante Gnerre ◽

...

Keyword(s):

Homologous Recombination ◽

Copy Number ◽

Circulating Tumor Dna ◽

Homologous Recombination Repair ◽

Copy Number Loss ◽

Recombination Repair ◽

Repair Genes ◽

Tumor Dna

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Abstract 435: Cell-free circulating tumor DNA (ctDNA) detects somatic copy number loss in homologous recombination repair genes

10.1158/1538-7445.am2019-435 ◽

2019 ◽

Author(s):

Catalin Barbacioru ◽

Victoria M. Raymond ◽

Marcin Sikora ◽

Elena Helman ◽

Sante Gnerre ◽

...

Keyword(s):

Homologous Recombination ◽

Copy Number ◽

Circulating Tumor Dna ◽

Homologous Recombination Repair ◽

Copy Number Loss ◽

Recombination Repair ◽

Repair Genes ◽

Tumor Dna

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Clinical Implications of DNA Repair Defects in High-Grade Serous Ovarian Carcinomas

Cancers ◽

10.3390/cancers12051315 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1315 ◽

Cited By ~ 1

Author(s):

Michela Camilla Milanesio ◽

Silvia Giordano ◽

Giorgio Valabrega

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Parp Inhibitors ◽

High Grade ◽

Ovarian Carcinomas ◽

Ovarian Cancers ◽

Mutational Status

Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the “the Achille’s heel” of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients’ survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient’s bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.

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Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-0066 ◽

2013 ◽

Vol 19 (13) ◽

pp. 3474-3484 ◽

Cited By ~ 54

Author(s):

Joshy George ◽

Kathryn Alsop ◽

Dariush Etemadmoghadam ◽

Heather Hondow ◽

Thomas Mikeska ◽

...

Keyword(s):

Gene Expression ◽

Copy Number ◽

High Grade ◽

Copy Number Alterations ◽

Brca1 And Brca2 ◽

Ovarian Cancers ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

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Tissue- and development-stage–specific mRNA and heterogeneous CNV signatures of human ribosomal proteins in normal and cancer samples

Nucleic Acids Research ◽

10.1093/nar/gkaa485 ◽

2020 ◽

Author(s):

Anshuman Panda ◽

Anupama Yadav ◽

Huwate Yeerna ◽

Amartya Singh ◽

Michael Biehl ◽

...

Keyword(s):

Cell Lines ◽

Copy Number ◽

Ribosomal Proteins ◽

Development Stage ◽

Ribosome Profiling ◽

Copy Number Loss ◽

Mrna Levels ◽

Cell Of Origin ◽

Tissue Specific ◽

Protein Levels

Abstract We give results from a detailed analysis of human Ribosomal Protein (RP) levels in normal and cancer samples and cell lines from large mRNA, copy number variation and ribosome profiling datasets. After normalizing total RP mRNA levels per sample, we find highly consistent tissue specific RP mRNA signatures in normal and tumor samples. Multiple RP mRNA-subtypes exist in several cancers, with significant survival and genomic differences. Some RP mRNA variations among subtypes correlate with copy number loss of RP genes. In kidney cancer, RP subtypes map to molecular subtypes related to cell-of-origin. Pan-cancer analysis of TCGA data showed widespread single/double copy loss of RP genes, without significantly affecting survival. In several cancer cell lines, CRISPR-Cas9 knockout of RP genes did not affect cell viability. Matched RP ribosome profiling and mRNA data in humans and rodents stratified by tissue and development stage and were strongly correlated, showing that RP translation rates were proportional to mRNA levels. In a small dataset of human adult and fetal tissues, RP protein levels showed development stage and tissue specific heterogeneity of RP levels. Our results suggest that heterogeneous RP levels play a significant functional role in cellular physiology, in both normal and disease states.

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