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A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]

ABSTRACT: Heterozygous germline mutations in BRCA1 or BRCA2 predispose to breast, ovarian, as well as other cancers. The main physiological function of BRCA1 and BRCA2 is to facilitate DNA replication, by stabilising and re-starting stalled replication forks. Consequently, inactivation of either BRCA1 or BRCA2 genes leads to replication pathologies and accumulation of DNA double strand breaks. Similar to BRCA1/2 inactivation, oncogene overexpression interferes with replication and inflicts DNA damage. It remains unclear how the replication defects in the two settings differ from each other and what is their combined effect on cell viability. Here, we report that accumulation of β-catenin, an oncogene of the WNT signalling pathway, is synthetically lethal with BRCA1/2 inactivation. We identify two transcription-dependent mechanisms that mediate oncogene toxicity in the context of BRCA1/2 deficiency. Firstly, accumulation of β-catenin activates E2F-dependent transcription, which accelerates G1/S transition, thus counteracting the delayed S-phase entry caused by BRCA1/2 abrogation. This, in turn, triggers illegitimate origin firing leading to fork collapse, DNA damage and deregulation of gene expression. Secondly, we find that β-catenin accumulation suppresses transcription of CDKN1A gene encoding p21, a modulator of fork progression. Decreased replication rates represent a hallmark of BRCA2 deficiency. Through p21 downregulation, β-catenin accelerates replication fork progression in BRCA2-deficient cells, thereby inflicting DNA damage and triggering cell death. Thus, our results demonstrate that oncogene-driven premature S-phase entry and increased replication rate are lethal in the context of BRCA1/2 abrogation, which explains the mutual exclusivity between oncogene activation and BRCA1/2 gene mutations in human tumours.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153735 | GEO | 2021/04/01

REPOSITORIES: GEO

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Project description:The proteins from the Fanconi Anemia (FA) pathway of DNA repair maintain DNA replication fork integrity by preventing the unscheduled degradation of nascent DNA at regions of stalled replication forks. Here, we ask if the bacterial pathogen H. pylori exploits the fork stabilisation machinery to generate double stand breaks (DSBs) and genomic instability. Specifically, we study if the H. pylori virulence factor CagA generates host genomic DSBs through replication fork destabilisation and collapse. An inducible gastric cancer model was used to examine global CagA-dependent transcriptomic and proteomic alterations, using RNA sequencing and SILAC-based mass spectrometry, respectively. The transcriptional alterations were confirmed in gastric cancer cell lines infected with H. pylori. Functional analysis was performed using chromatin fractionation, pulsed-field gel electrophoresis (PFGE), and single molecule DNA replication/repair fiber assays. We found a core set of 31 DNA repair factors including the FA genes FANCI, FANCD2, BRCA1, and BRCA2 that were downregulated following CagA expression. H. pylori infection of gastric cancer cell lines showed downregulation of the aforementioned FA genes in a CagA-dependent manner. Consistent with FA pathway downregulation, chromatin purification studies revealed impaired levels of Rad51 but higher recruitment of the nuclease MRE11 on the chromatin of CagA-expressing cells, suggesting impaired fork protection. In line with the above data, fibre assays revealed higher fork degradation, lower fork speed, daughter strands gap accumulation, and impaired re-start of replication forks in the presence of CagA, indicating compromised genome stability. By downregulating the expression of key DNA repair genes such as FANCI, FANCD2, BRCA1, and BRCA2, H. pylori CagA compromises host replication fork stability and induces DNA DSBs through fork collapse. These data unveil an intriguing example of a bacterial virulence factor that induces genomic instability by interfering with the host replication fork stabilisation machinery.

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A transcription-based mechanism for oncogene-induced lethality in BRCA1/2-deficient cells [RNA-seq]

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