A5102912153- DNA Repair Mechanisms
- Immune Cell Function and Interaction
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- T-cell and B-cell Immunology
- PARP inhibition in cancer therapy
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- thermodynamics and calorimetric analyses
- Heat shock proteins research
- Genetics, Aging, and Longevity in Model Organisms
- Chronic Lymphocytic Leukemia Research
- Cytomegalovirus and herpesvirus research
- Viral-associated cancers and disorders
- Physiological and biochemical adaptations
- RNA Research and Splicing
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- CAR-T cell therapy research
- NF-κB Signaling Pathways
- Genetic Neurodegenerative Diseases
- DNA and Nucleic Acid Chemistry
- Immunotherapy and Immune Responses
- MicroRNA in disease regulation
- Animal Genetics and Reproduction
National Cancer Institute
2014-2024
National Institutes of Health
2011-2023
National Human Genome Research Institute
2020-2023
Center for Cancer Research
2014-2023
National Heart Lung and Blood Institute
2005
Memorial Sloan Kettering Cancer Center
1995-1998
Rockefeller University
1996
Massachusetts Institute of Technology
1996
Howard Hughes Medical Institute
1996
Double-strand break (DSB) damage in yeast and mammalian cells induces the rapid ATM (ataxia telangiectasia mutated)/ATR Rad3 related)-dependent phosphorylation of histone H2AX (γ-H2AX). In budding yeast, a single endonuclease-induced DSB triggers γ-H2AX modification 50 kb on either side DSB. The extent spreading does not depend chromosomal sequences. DNA resection after formation causes slow, progressive loss from single-stranded and, several hours, Mec1 (ATR)-dependent to more distant...
Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic replication. Mice deficient both a nonhomologous end joining (NHEJ) repair protein p53 tumor suppressor develop lymphomas at an early age harboring amplification IgH/c-myc fusion. Here we report these...
Posttranslational modifications of histone tails regulate numerous biological processes including transcription, DNA repair, and apoptosis. Although recent studies suggest that structural alterations in chromatin are critical for triggering the damage response, very little is known about nature damage-induced perturbations. Here we show serine 14 residue NH2-terminal tail H2B rapidly phosphorylated at sites double-strand breaks. At late time points after irradiation, form H2B, H2B-Ser14P,...
Immunoglobulin (Ig) isotype switching is a recombination event that changes the constant domain of antibody genes and catalyzed by activation-induced cytidine deaminase (AID). Upon recruitment to Ig genes, AID deaminates cytidines at switch (S) sites, leading formation DNA breaks. In addition their role in switching, AID-induced lesions promote Igh-cMyc chromosomal translocations tumor development. However, cMyc are also present lymphocytes from healthy humans mice, thus, it remains unclear...
Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited division in vivo. Here, we report an epigenetic mechanism regulating self-renewal. The recruitment of PI3K-related kinase signaling pathway histone H2AX phosphorylation following GABA(A) receptor activation limits subventricular zone proliferation. As a result, NSC niche size can be directly modulated both directions pharmacologically or by genetically targeting activation....
Unmethylated CpG motifs present in bacterial DNA stimulate a strong innate immune response. There is evidence that DNA-dependent protein kinase (DNA-PK) mediates signaling. Specifically, wortmannin (an inhibitor of phosphatidylinositol 3 [PI3]-kinases including DNA-PK) interferes with CpG-dependent cell activation, and DNA-PK knockout (KO) mice fail to respond stimulation. Current studies establish actually inhibits the uptake colocalization toll-like receptor (TLR)-9 endocytic vesicles,...
Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, instability, and cancer predisposition, all of which may be the result abnormal signal transduction during DNA damage recognition. Here, we show that BLM an intermediate responder to stalled replication forks. colocalized physically interacted with response proteins 53BP1 H2AX. Although facilitated physical interaction between p53 53BP1, was required for efficient accumulation both at...
Chemotherapy-resistant acute myeloid leukemia may respond to inhibition of ATR or ATM.
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...
In Saccharomyces cerevisiae , absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase activity ribonucleotide reductase (RNR) complex. Whether this pathway conserved in mammals remains unknown. Here we show cells from mice carrying extra alleles RNR regulatory subunit RRM2 ( Rrm2 TG ) present supraphysiological and reduced chromosomal breakage at fragile sites. Moreover, increased gene dosage significantly extends life span ATR mutant mice. Our study reveals first...
Genome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control DNA repair outcomes hinders its therapeutic potential. especially understudied in nondividing cells like neurons, which must withstand decades damage without replicating. This lack knowledge limits the efficiency precision genome clinically relevant cells. To address this, we used induced pluripotent stem (iPSCs) iPSC-derived neurons examine how postmitotic human Cas9-induced damage....