LARP7 is a substrate of BRCA1 that regulats genome instability and tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA511893 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8370570_1.fastq.gz | Fastqsanger.gz | |||
| SRR8370570_2.fastq.gz | Fastqsanger.gz | |||
| SRR8370571_1.fastq.gz | Fastqsanger.gz | |||
| SRR8370571_2.fastq.gz | Fastqsanger.gz | |||
| SRR8370572_1.fastq.gz | Fastqsanger.gz |
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Project description:Impaired DNA repair leads to cancer, aging and many genetic diseases. However, understanding of the complexity of DNA is far from complete, resulting in the failure of therapies using genotoxic reagents. Here, we found that LARP7, an RNA-binding protein known to stabilize 7SK RNA, was degraded after DNA injury caused by ionizing radiation and chemotherapy. The LARP7 degradation was catalyzed by an E3 ligase complex of BRCA1 and BARD1 that was triggered by ATM-mediated phosphorylation. LARP7 depletion caused transcriptional repression of the cell cycle regulators CCNB1, CCNB2 and CDK1; this repression arrested cells before the G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation, therefore enhancing Rad51 recruitment and ultimately ensuring the homologous repair of damaged DNA. Importantly, the increased DNA damage repair capacity induced by LARP7 depletion caused resistance to ionizing radiation and CDDP treatment in both wild-type and BRCA1-mutant breast cancer cells and in mouse xenografts. Such resistance also contributed to reduced relapse-free survival rates in breast cancer patients with low levels of LARP7 after chemotherapy. Taken together, the results of this study show that LARP7 coordinates cell cycle progression and faithful DNA repair. We suggest that this mechanism could be exploited to prevent tumorigenesis and improve the effectiveness of cancer therapies.
2019-01-01 | GSE124393 | GEO
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie Dropseq.
2021-11-17 | GSE148566 | GEO
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie single cell RNA sequencing.
2021-11-17 | GSE148569 | GEO
Project description:Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
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Project description:Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in DNA repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. Cell culture-based studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcriptional regulation and genetic instability. We found that BRCA1 mutation-associated R-loop accumulates preferentially in luminal epithelial cells of cancer-free human breast tissue, and at the 5' end of those genes that experience promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of mouse NELF-B/COBRA1, a Pol II-pausing factor and BRCA1-binding protein, in Brca1 knockout mouse mammary epithelium ameliorates R-loop accumulation and reduces mammary tumorigenesis. Our studies show that Pol II pausing is a previously unappreciated contributor to BRCA1-associated R-loop accumulation and breast cancer development.
2017-06-27 | GSE96672 | GEO
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie RNA sequencing.
2021-11-17 | GSE148565 | GEO
Project description:Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis
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Project description:In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.
2025-04-23 | GSE288315 | GEO
Project description:In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.
2025-04-23 | GSE200444 | GEO
Project description:Meiotic sex chromosome inactivation (MSCI) is an essential event in meiotic progression in mammalian spermatogenesis. We found that La Ribonucleoprotein 7 (LARP7) is involved in MSCI. LARP7 plays a role in fetal germ cells to promote their proliferation, but is once abolished in postnatal gonocytes and re-expresses in spermatocytes at the onset of meiosis. In spermatocytes, LARP7 localizes to the XY body, a compartmentalized chromatin domain on sex chromosomes. This study aimed to elucidate a possible function of LARP7 in the XY body by using germline-specific Larp7-deficient mice.
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