FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress
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ABSTRACT:
PROVIDER: PRJNA972728 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24576373_1.fastq.gz | Fastqsanger.gz | |||
| SRR24576373_2.fastq.gz | Fastqsanger.gz | |||
| SRR24576374_1.fastq.gz | Fastqsanger.gz | |||
| SRR24576374_2.fastq.gz | Fastqsanger.gz | |||
| SRR24576375_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. Here, we report that upon replication stress, phosphorylation of the FANCD2 N-terminus by CHK1 triggers FBXL12-dependent proteasomal degradation of FANCD2, facilitating clearance of FANCD2 at stalled replication forks. This mechanism is required to promote efficient and faithful DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Notably, reconstitution of FANCD2 with mutations in the N-terminal phosphodegron fail to re-establish fork progression in FANCD2-deficient human fibroblasts in response to replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, CYCLIN E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification of FBXL12 is linked to reduced survival in patients with high CYCLIN E expressing breast tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability of CYCLIN E-overexpressing cancer cells and may represent a novel target for cancer therapy.
2023-08-16 | GSE232558 | GEO
Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to
overcome to progress towards malignancy. Fanconi anaemia signalling represents a major
genomic maintenance pathway that is activated in response to replication stress, impinging on
stalled replication fork stability and recovery. Here, we report that FBXL12 ubiquitinates the
central Fanconi anaemia protein FANCD2 at stalled replication forks upon CHK1-mediated
phosphorylation, resulting in FANCD2 degradation. This mechanism is required to promote
efficient and faithful DNA replication under conditions of cyclin E- and drug-induced
replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading
to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, cyclin
E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification
of FBXL12 is linked to reduced survival in patients with high cyclin E expressing breast
tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and
sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition.
Collectively, our results indicate that FBXL12 constitutes a vulnerability of cyclin E-
overexpressing cancer cells and represents a novel target for cancer therapy.
2023-05-22 | MSV000092004 | MassIVE
Project description:Genome-wide distribution of FANCD2 protein in chromatin under replication stress.
2018-01-20 | GSE104464 | GEO
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells
2013-06-27 | E-GEOD-46902 | biostudies-arrayexpress
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.
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Project description:Vertebrate DNA crosslink repair excises toxic replication-blocking DNA crosslinks. Numerous factors involved in crosslink repair have been identified, and mutations in their corresponding genes cause Fanconi anemia (FA). A key step in crosslink repair is monoubiquitination of the FANCD2-FANCI heterodimer, which then recruits nucleases to remove the DNA lesion. In this study, monoubiquitinated FANCD2-FANCI complex was characterized using crosslinking mass spectrometry in order to provide in sights into the 3D structure of the complex.
2020-03-09 | PXD017020 | Pride
Project description:To investigate the cooperative function of FANCD2/SRSF1 complex in the regulation of R-loops, we performed gene expression, isoform and splicing analysis in Hela cells depleted of SRSF1 or expressing SRSF1 mutants and FA-D2 mutant (FA-D2) and wild type (FA-D2+FANCD2) cells.
2024-02-26 | GSE212471 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions
2022-09-07 | GSE210163 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions
2022-09-07 | GSE205583 | GEO
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions
2022-09-07 | GSE205584 | GEO