A5091046972- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Cancer-related Molecular Pathways
- Genetic Neurodegenerative Diseases
- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- Retinal Development and Disorders
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Viral gastroenteritis research and epidemiology
- Connexins and lens biology
- Connective tissue disorders research
- Helicobacter pylori-related gastroenterology studies
- Aldose Reductase and Taurine
- Veterinary medicine and infectious diseases
- Neurogenesis and neuroplasticity mechanisms
- RNA Research and Splicing
- Moyamoya disease diagnosis and treatment
- Corneal Surgery and Treatments
- Heat shock proteins research
- Kruppel-like factors research
- DNA and Nucleic Acid Chemistry
National Human Genome Research Institute
2022-2025
National Cancer Institute
2022-2025
University College London
2024
Montreal Neurological Institute and Hospital
2024
The University of Texas Southwestern Medical Center
2024
McGill University
2024
National Hospital for Neurology and Neurosurgery
2024
Institut Cochin
2020-2023
Université Paris Cité
2020-2023
Inserm
2020-2023
Neurons harbor high levels of single-strand DNA breaks (SSBs) that are targeted to neuronal enhancers, but the source this endogenous damage remains unclear. Using two systems postmitotic lineage specification-induced pluripotent stem cell-derived neurons and transdifferentiated macrophages-we show thymidine glycosylase (TDG)-driven excision methylcytosines oxidized with ten-eleven translocation enzymes (TET) is a SSBs. Although macrophage differentiation favors short-patch base repair fill...
Using CRISPR-Cas9 nicking enzymes, we examined the interaction between replication machinery and single-strand breaks, one of most common forms endogenous DNA damage. We show that fork collapse at leading-strand nicks generates resected single-ended double-strand breaks (seDSBs) are repaired by homologous recombination (HR). If these seDSBs not promptly repaired, arrival adjacent forks creates double-ended DSBs (deDSBs), which could drive genomic scarring in HR-deficient cancers. deDSBs can...
Abstract CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n in the RFC1 gene. There are multitude motifs found human population at this locus, some which pathogenic and others benign. In study, we conducted structure-functional analyses nonpathogenic (A4G)n repeats. We that pathogenic, but not nonpathogenic, presents potent, orientation-dependent impediment to DNA polymerization vitro. The pattern blockage...
Abstract Cells are inevitably challenged by low-level/endogenous stresses that do not arrest DNA replication. Here, in human primary cells, we discovered and characterized a noncanonical cellular response is specific to nonblocking replication stress. Although this generates reactive oxygen species (ROS), it induces program prevents the accumulation of premutagenic 8-oxoguanine an adaptive way. Indeed, stress-induced ROS (RIR) activate FOXO1-controlled detoxification genes such as SEPP1,...
Myc protooncogenes play important roles in the regulation of cell proliferation, growth, differentiation and survival during development. In various developing organs, c-myc has been shown to control expression cycle regulators its misregulated is detected many human tumors. Here, we show that gene (Myc) highly expressed mouse lens. Targeted deletion from head surface ectoderm dramatically impaired ocular organogenesis, resulting severe microphtalmia, defective anterior segment development,...
Abstract Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays key roles in genome stability and variability due to its DNA double-strand break interstrand crosslink repair, the protection resumption arrested replication forks. HR deficiency leads genetic instability, and, as expected, many genes are downregulated The link between predisposition exemplified by familial breast ovarian cancers some subgroups Fanconi anaemia syndromes. Surprisingly, although...
ABSTRACT Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause irreversible blindness. Thus, therapeutic strategies are needed to protect and replace these projection neurons. One innovative approach promote de novo genesis RGCs via manipulation endogenous sources. Here, we demonstrate that pluripotency regulator gene Krüppel-like factor 4 (Klf4) sufficient change potency lineage-restricted retinal progenitor cells generate in vivo. Transcriptome...
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...
The number of GAA repeats in the FXN gene is a major but not sole determinant clinical presentation Friedreich ataxia (FRDA). objective this study was to establish whether length repeat tract FGF14 gene, which associated with another neurodegenerative disorder (SCA27B), affects (age at onset, mFARS score) patients FRDA. and genes determined using PCR cohort 221 Next, we compared absolute lengths GAAs GAAs, followed by correlative analyses determine potential effects on age onset (mFARS) We...
The unique eyes of the four-eyed fish Anableps anableps have long intrigued biologists. Key features associated with bulging eye include expanded frontal bone and duplicated pupils cornea. Furthermore, retina expresses different photoreceptor genes in dorsal ventral regions, potentially distinct aerial aquatic stimuli. To gain insight into developmental basis eye, we examined neurocranium ontogeny, as well gene expression during larval stages. First, described six stages which duplication...
Somatic hypermutation (SHM) and class switch recombination (CSR) diversify immunoglobulin (Ig) genes are initiated by the activation induced deaminase (AID), a single-stranded DNA cytidine that is thought to engage its substrate in context of RNA polymerase II (RNAPII) transcription. Through loss function genetic screen, we identified numerous potential factors involved SHM including ELOF1, component RNAPII elongation complex has been shown repair transcription elongation. Loss ELOF1...
Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss largely restricted to the cerebellum. Although locus highly unstable during intergenerational transmission, it remains unknown whether exhibits cerebral mosaicism and progressive instability throughout life. We conducted analysis of FGF14 somatic across 156 serial blood samples from 69 individuals, fibroblasts,...
Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that characterized by growth retardation and neurodevelopmental defects, including reports retinopathy. Mutations in key mediators the replication stress response, mutually dependent partners ATR ATRIP, are among known causes syndrome. However, it remains unclear how their deficiency disrupts development function central nervous system (CNS). Here, we investigated cellular molecular consequences ATRIP different cell...
Abstract The maintenance of genomic stability during the cell cycle progenitor cells is essential for faithful transmission genetic information. Mutations in genes that ensure genome lead to human developmental syndromes. Ataxia Telangiectasia and Rad3-related ( ATR ) or ATR-interacting protein ATRIP Seckel syndrome, which characterized by malformations short life expectancy. While roles replicative stress response chromosomal segregation are well established, it unknown how contributes...
Genomic instability in the central nervous system (CNS) is associated with defective neurodevelopment and neurodegeneration. Congenital human syndromes that affect CNS development originate from mutations genes of DNA damage response (DDR) pathways. RINT1 (Rad50-interacting protein 1) a partner RAD50, participates cellular responses to double-strand breaks (DSB). Recently, we showed Rint1 regulates cell survival developing brain its loss led premature lethality genomic stability. To bypass...
Summary Genomic double-stranded DNA (dsDNA) becomes single-stranded (ssDNA) during replication, transcription, and repair. ssDNA is therefore believed to be transient, occurring in only a fraction of the genome at given time, variable amongst population cells. These transiently formed segments can also adopt alternative, dynamic conformations, such as cruciform DNA, triplexes, quadruplexes others. To determine whether there are stable conserved regions ssDNA, we utilized our previously...
CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A