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Transcription-Replication Conflicts drive the Synthetic Lethality of PARP Inhibitors with BRCA2-Deficiency

ABSTRACT: To examine replication fork progression firing upon TIMELESS/TIPIN knockdown, EdUseq was performed in HeLa cells transfected with siCTRL, siTIMELESS or siTIPIN, synchronised with Thymidine and then released for 120 min in S phase, with the last 30 minutes being labeled with EdU.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220223 | GEO | 2024/04/12

REPOSITORIES: GEO

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The mismatch recognition protein MutSalpha promotes nascent strand degradation at stalled replication forks

Project description:Regular iPOND: 707789: C3-4 EdU, 707790: C3-4 Thymidine chase, 707791: A3-6 EdU, 707792: A3-6 Thymidine chase. SILAC iPOND: 1002641. Regular iPOND: WT MEF cell line (C3-4) and P286R MEF cells (A3-6) were labeled with EdU with (C3-4/A3-6 Thymidine chase) or without thymidine chase (C3-4/A3-6 EdU). Click reaction was performed to link a biotin to the EdU followed by pull down with streptavidin beads. SILAC iPOND: P286R MEF cells (abundance 1002641 Light) were cultured in "light" medium containing [12C14N]-L-lysine and [12C14N]-L-arginine, and WT MEF cells (Abundance 1002641 Heavy) were cultured in "heavy" medium containing [13C15N]-L-lysine [13C15N]-L-arginine. After more than 99% cells were labeled with isotopes, equal amount of WT and P286R cells were combined followed by EdU labeling and click reaction. Proteins captured were dissolved on SDS/PAGE and subjected to MS analysis.

| MSV000090330 | MassIVE

Nucleotide Excision Repair Removes Thymidine Analog 5-Ethynyl-2’-deoxyuridine From the Human Genome

Project description:5-Ethynyl-2’-deoxyuridine (EdU) is one of the several thymidine analogs that are used in labeling DNA in cells and in DNA combing (DNA fiber analysis) to study DNA replication1-5. We wished to use these analogs to investigate the repair complex (DNA-protein) of nucleotide excision repair. UV irradiated human cell lines were incubated with EdU, BrdU, IdU, CldU, F-ara-EdU or AmdU to incorporate these analogs into the 26-27 nucleotide long excision repair products. Unexpectedly, we found that EdU even in the absence of DNA damage was released in the form of 26-27nt-long oligomers. We conclude that EdU is incorporated into replicating DNA and is recognized as damage by the nucleotide excision repair system and removed from the genome followed by repair synthesis and re-incorporation into DNA, thus creating futile cycle that leads to cell death. This property of EdU, which was not seen with any of the other thymidine analogs, may be taken advantage of in treating cancer, in particular brain cancers because EdU crosses blood-brain barrier.

2022-08-02 | GSE202784 | GEO

A high-resolution, nanopore-based artificial intelligence assay for DNA replication stress in human cancer cells

Project description:Human cancer cell lines were pulsed with thymidine analogues EdU and BrdU, sequenced on the Oxford Nanopore platform, and analysed with our DNAscent software to measure DNA replication stress.

2024-04-01 | GSE216926 | GEO

Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in <i>BRCA2</i>-altered Prostate Tumors.

Project description: Not available

| S-EPMC7956224 | biostudies-literature

Separable functions of Tof1/Timeless in intra-S-checkpoint signalling, replisome stability and DNA topological stress

Project description:The highly conserved Tof1/Timeless proteins minimise replication stress and promote normal DNA replication. They are required to mediate the DNA replication checkpoint (DRC), the stable pausing of forks at protein fork blocks, the coupling of DNA helicase and polymerase functions during replication stress (RS) and the preferential resolution of DNA topological stress ahead of the fork. Here we demonstrate that the roles of the Saccharomyces cerevisiae Timeless protein Tof1 in DRC signalling and resolution of DNA topological stress require distinct N and C terminal regions of the protein, whereas the other functions of Tof1 are closely linked to the stable interaction between Tof1 and its constitutive binding partner Csm3/Tipin. By separating the role of Tof1 in DRC from fork stabilisation and coupling, we show that Tof1 has distinct activities in checkpoint activation and replisome stability to ensure the viable completion of DNA replication following replication stress.

2020-10-08 | GSE144321 | GEO

PARP inhibitors: Synthetic lethality in the clinic.

Project description: Not available

| S-EPMC6175050 | biostudies-literature

LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL.

Project description: Not available

| S-EPMC6752209 | biostudies-literature

Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.

Project description: Not available

| S-EPMC3551628 | biostudies-literature

Synthetic Lethality of PARP Inhibition and Ionizing Radiation is p53-dependent.

Project description: Not available

| S-EPMC6713455 | biostudies-literature

Amplification of mutant BRCA2 gene confers resistance to PARP inhibitor

Project description:Breast cancer gene 2 (BRCA2) deleterious mutations confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to its critical role in DNA repair. PARP inhibitor Olaparib is now approved and several other PARP inhibitors are now in different stages of clinical trials. Development of resistance to PARP inhibitors limits their clinical utility. The mechanism of resistance remains not fully understood. Here we show that amplification of mutant BRCA2 confers PARP inhibitor resistance. The amplification of mutant BRCA2 gene copies correlates with an increase in mutant BRCA2 expression and an increase in the levels of its interacting proteins PALB2 and RAD51. In addition, homologous recombination mediated DNA repair is rescued in these cells as evidenced by the formation of RAD51 focus formation. The overexpressed mutant BRCA2 is essential for the observed PARP inhibitor resistance because knockdown of its expression is sufficient to re-sensitize these cells to PARP inhibition. Collectively, our results indicate a new mechanism of resistance to PARP inhibitor in BRCA2 mutant cancer cells

2017-09-02 | GSE86394 | GEO

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