A5062948253- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- Heat shock proteins research
- Advanced biosensing and bioanalysis techniques
- Circular RNAs in diseases
- Genetics and Neurodevelopmental Disorders
- MicroRNA in disease regulation
- Mitochondrial Function and Pathology
- Cancer-related Molecular Pathways
- Plant Genetic and Mutation Studies
- RNA Research and Splicing
- Chromosomal and Genetic Variations
- Genomics and Chromatin Dynamics
- DNA and Nucleic Acid Chemistry
- Genetic Neurodegenerative Diseases
- NF-κB Signaling Pathways
- RNA Interference and Gene Delivery
- Cell death mechanisms and regulation
- Amoebic Infections and Treatments
- Carcinogens and Genotoxicity Assessment
- Plant tissue culture and regeneration
St. Jude Children's Research Hospital
2013-2022
The University of Texas Health Science Center at San Antonio
2007-2011
The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit the DNA-dependent kinase, encoded by PRKDC ), ATM (ataxia telangiectasia, mutated), ATR (ATM Rad3-related) are related PI3K-like protein kinases central regulators DDR. Defects in these have been linked neurodegenerative neurodevelopmental syndromes. In all cases, key neuroprotective...
The pathogenesis of inherited genome instability neurodegenerative syndromes remains largely unknown. Here, we report new disease-relevant murine models instability–driven neurodegeneration involving disabled ATM and APTX that develop debilitating ataxia. We show ataxia result from transcriptional interference in the cerebellum via aberrant messenger RNA splicing. Unexpectedly, these splicing defects were restricted to only Purkinje cells, disrupting expression critical homeostatic...
Frequent oxidative modification of the neural genome is a by-product high oxygen consumption nervous system. Rapid correction DNA lesions essential, as stability paramount determinant homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known "APEX1" or "REF1") key enzyme for repair damage, although specific role(s) this in development and maintenance system largely unknown. Here, using conditional inactivation murine Ape1, we identify critical roles protein brain selectively after...
TREX2 is an autonomous nonprocessive 3′ → 5′ exonuclease, suggesting that it maintains genome integrity. To investigate TREX2's biochemical and cellular properties, we show endogenous expressed widely in mouse tissues human cell lines. Unexpectedly, predominantly as a 30-kDa protein (not 26 kDa, previously believed), which likely encoded by longer isoforms (TREX2L1 and/or TREX2L2) possess similar capacity for self-association, DNA binding catalytic activity. Site-directed mutagenesis...
Abstract Trex2 is a 3′ → 5′ exonuclease that removes 3′-mismatched sequences in biochemical assay; however, its biological function remains unclear. To address biology we previously generated trex2null mouse embryonic stem (ES) cells and expressed these wild-type human TREX2 cDNA (Trex2hTX2) or with single-amino-acid change the catalytic domain (Trex2H188A) DNA-binding (Trex2R167A). We found Trex2H188A exhibited spontaneous broken chromosomes chromosomal rearrangements. also ectopically was...
Abstract Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3′→5′ exonuclease removes 3′ mismatched nucleotides and promotes cellular proliferation. Here, we show depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating potential role for depletion cisplatin-induced cytotoxicity. To better understand function,...
The HPRT minigene is a selection cassette used for gene targeting in mouse embryonic stem (ES) cells and, it unique since may be applied its presence and absence. This has two exon clusters separated by small intron splicing sequences. We find these splice into exons from the target forming different classes of chimeric transcripts. first class expressed endogenous promoter includes upstream spliced 3-8. second minigene's PGK 1-2 downstream exons. These transcripts produce proteins that...
The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit the DNA-dependent kinase, encoded by <i>PRKDC</i>), ATM (ataxia telangiectasia, mutated), ATR (ATM Rad3-related) are related PI3K-like protein kinases central regulators DDR. Defects in these have been linked neurodegenerative neurodevelopmental syndromes. In all cases, key...
Abstract The Shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and REV7, shields DNA double strand breaks (DSBs) from nucleolytic resection. end-protecting activity promotes productive non-homologous end joining (NHEJ) in G1 but can threaten genome integrity during S-phase by blocking homologous recombination (HR). Curiously, the penultimate component, SHLD1 is one least abundant mammalian proteins. Here, we report that transcription factors THAP1, YY1 HCF1 bind directly to promoter, where...
<div>Abstract<p>Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3′→5′ exonuclease removes 3′ mismatched nucleotides and promotes cellular proliferation. Here, we show depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating potential role for depletion cisplatin-induced cytotoxicity. To better...
<div>Abstract<p>Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3′→5′ exonuclease removes 3′ mismatched nucleotides and promotes cellular proliferation. Here, we show depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating potential role for depletion cisplatin-induced cytotoxicity. To better...