A5011537993- DNA Repair Mechanisms
- Cancer-related Molecular Pathways
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Telomeres, Telomerase, and Senescence
- Advanced Breast Cancer Therapies
- Neuroendocrine Tumor Research Advances
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Protist diversity and phylogeny
- Identification and Quantification in Food
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Nuclear Structure and Function
- Carcinogens and Genotoxicity Assessment
- Endoplasmic Reticulum Stress and Disease
- Chromosomal and Genetic Variations
- Molecular Biology Techniques and Applications
- Radiation Therapy and Dosimetry
- Cancer therapeutics and mechanisms
Centre National de la Recherche Scientifique
2014-2024
Sorbonne Université
2014-2024
Institut Gustave Roussy
2016-2024
Laboratoire d'études sur les monothéismes
2016-2024
Université Sorbonne Nouvelle
2024
Université Paris 1 Panthéon-Sorbonne
2023
Université Paris Sciences et Lettres
2016-2019
Sorbonne University Abu Dhabi
2019
Université Paris Cité
2014-2016
Institut Curie
2006-2016
Correct replication of the genome and protection its integrity are essential for cell survival. In a high-throughput screen studying H2AX phosphorylation, we identified Wee1 as regulator genomic stability. down-regulation not only induced phosphorylation but also triggered general deoxyribonucleic acid (DNA) damage response (DDR) caused block in DNA replication, resulting accumulation cells S phase. Wee1-deficient showed decrease fork speed, demonstrating involvement replication. Inhibiting...
Breaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, lymphocytes fibroblasts, that moderate replication stresses like those inducing breaks CFSs trigger chromatin loading sensors mediators the ATR pathway fail to activate Chk1 or p53. Consistently, found depleted ATR, not Chk1, accumulate single-stranded DNA upon Mre11-dependent...
Abstract Common fragile sites (CFSs) are chromosome regions prone to breakage upon replication stress known drive rearrangements during oncogenesis. Most CFSs nest in large expressed genes, suggesting that transcription could elicit their instability; however, the underlying mechanisms remain elusive. Genome-wide timing analyses here show stress-induced delayed/under-replication is hallmark of CFSs. Extensive genome-wide nascent transcripts, origin positioning and fork directionality reveal...
Highlights•Nuclease-dependent DNA damage events are induced in Chk1-deficient cells•Activation of the ATM pathway limits precursors available for replication•DNA precursor starvation elicits replication fork slowing these cells•Origin firing is fine-tuned by speed independently Chk1 statusSummaryMammalian cells deficient ATR or display moderate and increased initiation density, but underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both...
Faithful DNA replication is essential for the maintenance of genome integrity.Incomplete leads to breaks and chromosomal rearrangements, which are causal factors in cancer other human diseases.Despite their importance, molecular mechanisms that control stability incompletely understood.Here, we report a pathway required stability.This has three components: an E3 ubiquitin ligase, transcriptional repressor, protein.The ligase RBBP6 ubiquitinates destabilizes repressor ZBTB38.This negatively...
Proliferating cell nuclear antigen is best known as a DNA polymerase accessory protein but has more recently also been shown to have different functions in important cellular processes such replication, repair, and cycle control. PCNA found quaternary complexes with the cyclin kinase inhibitor p21 several pairs of cyclin-dependent kinases their regulatory partner, cyclins. Here we show direct interaction between Cdk2. This involves regions trimer close C termini. We that Cdk2 form complex...
The subunit that mediates binding of proliferating cell nuclear antigen (PCNA) to human DNA polymerase delta has not been clearly defined. We show the third delta, p66, interacts with PCNA through a canonical PCNA-binding sequence located in its C terminus. Conversely, p66 domain-interconnecting loop PCNA, region previously shown be important for activity and cycle inhibitor p21(Cip1). In accordance this, peptide containing domain p21(Cip1) inhibited native three-subunit delta. Furthermore,...
DNA replication control is a key process in maintaining genomic integrity. Monitoring initiation particularly important as it needs to be coordinated with other cellular events and should occur only once per cell cycle. Crucial players the of are ORC protein complex, marking origin replication, Cdt1 Cdc6 proteins, that license these origins replicate by recruiting MCM2‐7 helicase. To accurately achieve its functions, tightly regulated. levels high from metaphase during G1 low S/G2 phases...
Homologous recombination (HR) is a prominent DNA repair pathway maintaining genome integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the implication of pivotal factor RAD51 on development remains puzzling. Particularly, no mouse models are available address role aging and carcinogenesis vivo. We engineered model with an inducible dominant-negative form (SMRad51) that suppresses RAD51-mediated without stimulating alternative mutagenic pathways. found vivo...
Summary Replication stress, a major hallmark of cancers, and ensuing genome instability source from impaired progression replication forks. The first line defense against fork slowing is compensation, long-described process that elicits firing otherwise dormant origins. It remains unclear whether compensation requires activation the DNA checkpoint or passively results lengthening window time during which origins can fire when slows, both. Using molecular combing we show here linear...
Heterochromatic regions render the replication process particularly difficult due to high level of chromatin compaction and presence repeated DNA sequences. In humans, through pericentromeric heterochromatin requires binding a complex formed by telomeric factor TRF2 helicase RTEL1 in order relieve topological barriers blocking fork progression. Since is known bind Origin Replication Complex (ORC), we hypothesized that this could also play role at origins (ORI) these regions. By performing...
Polymerase chain reaction (PCR) from paraffin-embedded tissues provides a powerful tool to amplify DNA variety of recent and archival material. Because samples is more degraded than fresh material, the amplification reference genes essential exclude false-negative results. This study describes use proliferative cell nuclear antigen (PCNA) gene as in range animal species humans. The PCNA-PCR fragment extending exon 5 through 6 including intervening intron gave reproducible pattern, with...
Objective Ionizing radiation generates genomic instability by promoting the accumulation of chromosomal rearrangements. The oncogenic translocation RET/PTC1 is present in more than 70% radiation-induced thyroid cancers. Both RET and CCDC6 , genes implicated are found within common fragile sites – regions prone to DNA breakage during slight replication stress. Given that irradiated cells become susceptible destabilization due replication-stress-related double-strand breaks (DSBs), we explored...