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Cytidine deaminase resolves replicative stress and protects pancreatic cancer from DNA-targeting drugs II

ABSTRACT: Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA synthesis and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies

ORGANISM(S): Homo sapiens

PROVIDER: GSE253837 | GEO | 2024/01/24

REPOSITORIES: GEO

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Cytidine deaminase resolves replicative stress and protects pancreatic cancer from DNA-targeting drugs

Project description:Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA synthesis and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies

2024-01-15 | GSE252544 | GEO

Cytidine deaminase resolves replicative stress and protects pancreatic cancer from DNA-targeting drugs I

2024-01-24 | GSE253662 | GEO

BLM complex composition in unperturbed cells

Project description:The Bloom syndrome DNA helicase BLM contributes to chromosome stability through its roles in double-strand break repair by homologous recombination and DNA replication fork restart during the replication stress response. Loss of BLM activity leads to Bloom syndrome, which is characterized by extraordinary cancer risk and small stature. Here, we have analyzed the composition of the BLM complex in unperturbed cells and identified a direct physical interaction with the Mcm6 subunit of the minichromosome maintenance (MCM) complex by co-immunopecipitations using endogenous and recombinant proteins as well as two-hybrid analysis.

2022-02-15 | PXD018823 | Pride

Transcription Restart Establishes Chromatin Accessibility after DNA Replication

Project description:Transcription Restart Establishes Chromatin Accessibility after DNA Replication

| PRJNA528325 | ENA

Replication forks proteomics reveals ATM-dependent rewiring of broken forks to promote restart

Project description:The fidelity of DNA replication is governed by a network of DNA repair mechanisms. Defects in replication fork protection can fuel genome instability in cancer, while also creating cancer-specific vulnerabilities. Here, we provide a comprehensive proteomic characterization of the replication fork response to topoisomerase 1 inhibition, a widely used mainstay chemotherapy. We reveal profound changes in the fork proteome and chromatin environment in response to seDSBs and topological stress, and classify fork repair factors according to their specificity for broken and stalled forks. These distinct fork responses also oppositely affect nucleosome occupancy and nuclear membrane interactions. ATM inhibition dramatically rewired the fork breakage response, revealing that ATM promotes HR-dependent fork restart by concomitantly promoting DNA-end resection and suppressing DSB associated protein ubiquitination and NHEJ. Together, this collection of damaged fork proteomes provides an ample resource to understand fork repair mechanisms and identify druggable targets and novel cancer vulnerabilities.

2021-01-15 | PXD018092 | Pride

DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

Project description:To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent ,signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability

2017-03-28 | MSV000080704 | MassIVE

DDX17 helicase promotes resolution of R-loop-mediated transcription-replication conflicts in human cells

Project description:R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid and displaced DNA strand. These structures can halt DNA replication when formed co- transcriptionally in the opposite orientation to replication fork progression. Recent studies have shown that replication forks stalled by co-transcription R-loops can be restarted by a mechanism involving fork cleavage by MUS81 endonuclease, followed by reactivation of transcription, and fork religation by the DNA ligase IV (LIG4)/XRCC4 complex. However, how R-loops are eliminated to allow the sequential restart of transcription and replication in this pathway remains elusive. Here, we identified the human DDX17 helicase as a factor that associates with R-loops and counteracts R-loop-mediated replication stress to preserve genome stability. We show that DDX17 unwinds RNA:DNA hybrids in vitro and promotes MUS81-dependent restart of R-loop-stalled forks in human cells in a manner dependent on its helicase activity. Loss of DDX17 helicase induces accumulation of R-loops and the formation of R-loop-dependent anaphase bridges and micronuclei. These findings establish DDX17 as a component of the MUS81-LIG4 pathway for resolution of R-loop-mediated transcription- replication conflicts, which may be involved in R-loop unwinding.

2022-11-02 | PXD034331 | Pride

The Bloom Syndrome Complex Senses RPA-Coated Single-Stranded DNA to Restart Stalled Replication Forks

Project description:The Bloom syndrome helicase BLM interacts with topoisomerase IIIa (TOP3A), RMI1 and RMI2 to form the BTR complex, which dissolves double Holliday junctions to produce non-crossover products during homologous recombination (HR). BLM also promotes DNA-end resection and stalled replication fork restart. However, it is still unclear how the activities of the BTR complex are regulated in cells. Here, we identify multiple highly conserved short linear peptide motifs within the BTR complex that interact cooperatively with RPA. Furthermore, we demonstrate that RPA-binding is essential for stable recruitment of BLM to DNA damage sites and for stalled fork restart, but not for its roles in HR. Disruption of RPA-binding thus constitutes a novel separation-of-function mutation of the BTR complex, and suggest a model in which BTR contains the intrinsic ability to measure levels of RPA-ssDNA at replication forks, which controls its recruitment and activation in response to replication stress.

2021-01-05 | PXD018322 | Pride

DONSON encodes a novel replication fork protection factor mutated in 2 microcephalic dwarfism.

2017-02-10 | PXD005690 | Pride

FBXL12 degrades FANCD2 to regulate stalled fork recovery and promote cancer cell survival under conditions of replication stress

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

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