The novel FIGNL1-interacting protein C1orf112 is synthetic lethal with ERCC6L and mediates RAD51 retention on chromatin
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB54793 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10128800.fastq.gz | Fastqsanger.gz | |||
| ERR10128900.fastq.gz | Fastqsanger.gz | |||
| ERR10129000.fastq.gz | Fastqsanger.gz | |||
| ERR10129100.fastq.gz | Fastqsanger.gz | |||
| ERR10128801.fastq.gz | Fastqsanger.gz |
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Project description:Joint DNA molecules are natural by-products of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, which compromise sister chromatid separation. The DNA translocase PICH (ERCC6L) plays a central role in UFB resolution. To better understand the genetic context rendering cells dependent on PICH, a genome-wide loss-of-function screen was performed to identify the genetic contexts in which cells become dependent on PICH. In addition to genes involved in DNA cohesion, centromere stability and DNA damage repair, we identified the uncharacterized protein C1orf112. We find that C1orf112 interacts with and stabilizes the AAA+ ATPase FIGNL1. Inactivation of either C1orf112 or FIGNL1 resulted in UFB formation, prolonged retention of RAD51 on chromatin, impaired replication fork dynamics, and consequently impaired genome maintenance. Combined, our data reveal that inactivation of C1orf112 or FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in DNA replication defects, and a dependency on PICH to preserve cell viability.
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Project description:RAD51 is a highly conserved DNA repair protein and is indispensable for the execution of homologous recombination, thereby participating in maintaining genomic stability. Since constitutive Rad51 knockout mice exhibit embryonic lethality, the physiological functions of RAD51, and the consequences of lacking it, are largely unknown. We herein demonstrated a critical role of RAD51 in postnatal liver development and regeneration. RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in liver-related diseases. We generated hepatocyte-specific Rad51 deletion mouse model (Rad51-CKO) to evaluate the function of RAD51 in liver development and regeneration.RAD51 deletion in postnatal hepatocytes results in aborted mitosis, global polyploidization, oxidative stress and cellular senescence. Remarkable liver fibrosis occurs as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice.The senescence-associated secretory phenotype in the livers of Rad51-CKO mice creates a niche that favors the activation and propagation of hepatic progenitor cells (HPCs) in which Rad51 is spared due to lack of Alb-Cre expression. The Rad51 functional HPCs and immature hepatocytes can thus proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. Our results thus demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The RAD51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis, impaired regeneration and hepatocellular carcinogenesis.
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Project description:RAD51 is a highly conserved DNA repair protein and is indispensable for the execution of homologous recombination, thereby participating in maintaining genomic stability. Since constitutive Rad51 knockout mice exhibit embryonic lethality, the physiological functions of RAD51, and the consequences of lacking it, are largely unknown. We herein demonstrated a critical role of RAD51 in postnatal liver development and regeneration. RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in liver-related diseases. We generated hepatocyte-specific Rad51 deletion mouse model (Rad51-CKO) to evaluate the function of RAD51 in liver development and regeneration.RAD51 deletion in postnatal hepatocytes results in aborted mitosis, global polyploidization, oxidative stress and cellular senescence. Remarkable liver fibrosis occurs as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice.The senescence-associated secretory phenotype in the livers of Rad51-CKO mice creates a niche that favors the activation and propagation of hepatic progenitor cells (HPCs) in which Rad51 is spared due to lack of Alb-Cre expression. The Rad51 functional HPCs and immature hepatocytes can thus proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. Our results thus demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The RAD51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis, impaired regeneration and hepatocellular carcinogenesis.
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Project description:Long non-coding RNAs (lncRNA) have been shown to play crucial roles in tumorigenesis. Little is known about lncRNA RAD51-AS1 in diseases. Here, we investigated the role of RAD51-AS1 in Epithelial ovarian cancer. Silencing RAD51-AS1 inhibited proliferation through cell cycle arrest and promotion in apoptosis, both in vitro and in vivo. But the mechanism of RAD51-AS1 downstream regulation remains unclear. In order to identify the downstream regulation of RAD51-AS1 in epithelial ovarian cancer, we used antisene oligotides targeting RAD51-AS1 / negative control to transfect Skov3.ip cells. Then, we used microarrays to identified differential expression genes and to look for possible target genes by knockdown RAD51-AS1 expression.
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Project description:RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. Our data suggest that in addition to playing roles in homologous recombination-mediated DNA double-strand break repair and replication fork processing, RAD51 is also implicated in the suppression of innate immunity. Thus, our study reveals a previously uncharacterized role of RAD51 in initiating immune signaling, placing it at the hub of new interconnections between DNA replication, DNA repair, and immunity.
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Project description:Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum-resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway Homologous Recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein-expression in-situ. In a discovery cohort (n=284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin-monotherapy SCOTROC4 clinical trial cohort (n=264), and was predominantly noted in HR-proficient cancers (Myriad HRDscore<42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in-vitro, while high-RAD51 tumours showed exclusion of cytotoxic-T-cells in-situ. Our findings highlight RAD51 expression as a determinant of platinum resistance, and suggest possible roles for therapy to overcome immune exclusion in high-RAD51 EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
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