A5001726646- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Carcinogens and Genotoxicity Assessment
- PARP inhibition in cancer therapy
- RNA and protein synthesis mechanisms
- Genomics and Chromatin Dynamics
- Bacterial Genetics and Biotechnology
- RNA Research and Splicing
- HER2/EGFR in Cancer Research
- Advanced Electron Microscopy Techniques and Applications
- Estrogen and related hormone effects
- Transgenic Plants and Applications
- Genetic factors in colorectal cancer
- RNA regulation and disease
- Viral Infectious Diseases and Gene Expression in Insects
- Advanced biosensing and bioanalysis techniques
- Connective Tissue Growth Factor Research
- Ocular Infections and Treatments
- Ubiquitin and proteasome pathways
- Microbial Metabolism and Applications
- Microtubule and mitosis dynamics
- Enzyme Production and Characterization
- Retinoids in leukemia and cellular processes
Lawrence Berkeley National Laboratory
2013-2025
Eastern Virginia Medical School
2024
Massachusetts Institute of Technology
2022
University of California, Berkeley
2007-2012
National Tsing Hua University
1978
Recent studies have implicated a poorly defined alternative pathway of nonhomologous end joining (alt-NHEJ) in the generation large deletions and chromosomal translocations that are frequently observed cancer cells. Here, we describe an interaction between two factors, hMre11/hRad50/Nbs1 (MRN) DNA ligase IIIα/XRCC1, been linked with alt-NHEJ. Expression IIIα association MRN IIIα/XRCC1 altered cell lines defective major NHEJ pathway. Most notably, damage induced these factors IV-deficient...
R-loops are three-stranded nucleic acid structures with both physiological and pathological roles in cells. R-loop imaging generally relies on detection of the RNA–DNA hybrid component these using S9.6 antibody. We show that use this antibody for can be problematic because it readily binds to double-stranded RNA (dsRNA) vitro vivo, giving rise nonspecific signal. In contrast, purified, catalytically inactive human RNase H1 tagged GFP (GFP-dRNH1) is a more specific reagent hybrids. GFP-dRNH1...
Abstract Polymerase theta (Polθ) acts in DNA replication and repair, its inhibition is synthetic lethal BRCA1 BRCA2-deficient tumor cells. Novobiocin (NVB) a first-in-class inhibitor of the Polθ ATPase activity, it currently being tested clinical trials as an anti-cancer drug. Here, we investigated molecular mechanism NVB-mediated inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational cellular assays, found NVB non-competitive ATP...
The xeroderma pigmentosum protein A (XPA) and replication (RPA) proteins fulfill essential roles in the assembly of preincision complex nucleotide excision repair (NER) pathway. We have previously characterized two interaction sites, one between XPA N-terminal (XPA-N) disordered domain RPA32 C-terminal (RPA32C), other with DNA binding (DBD) RPA70AB DBDs. Here, we show that mutations inhibit physical either site reduce NER activity biochemical cellular systems. Combining sites leads to an...
MutSbeta (MSH2-MSH3) mediates repair of insertion-deletion heterologies but also triggers triplet repeat expansions that cause neurological diseases. Like other DNA metabolic activities, interacts with proliferating cell nuclear antigen (PCNA) via a conserved motif (QXX(L/I)XXFF). We demonstrate MutSbeta-PCNA complex formation occurs an affinity approximately 0.1 microM and preferred stoichiometry 1:1. However, up to 20% complexes are multivalent under conditions where is in molar excess...
Processivity clamps such as proliferating cell nuclear antigen (PCNA) and the checkpoint sliding clamp Rad9/Rad1/Hus1 (9-1-1) act versatile scaffolds in coordinated recruitment of proteins involved DNA replication, cell-cycle control, repair. Association handoff DNA-editing enzymes, flap endonuclease 1 (FEN1), with are key processes biology, which incompletely understood from a mechanistic point view. We have used an integrative computational experimental approach to define assemblies FEN1...
XPG is a structure-specific endonuclease required for nucleotide excision repair (NER). incision defects result in the cancer-prone syndrome xeroderma pigmentosum, whereas truncating mutations of cause severe postnatal progeroid developmental disorder Cockayne syndrome. We show that interacts directly with WRN protein, which defective premature aging Werner syndrome, and two proteins undergo similar subnuclear redistribution S phase colocalize nuclear foci. The co-localization was observed...
Homologous recombination is needed for meiotic chromosome segregation, genome maintenance, and tumor suppression. RAD51AP1 (RAD51 associated protein 1) has been shown to interact with enhance the recombinase activity of RAD51. Accordingly, genetic ablation leads enhanced sensitivity also aberrations upon DNA damage, demonstrating a role in mitotic homologous recombination. Here we show physical association meiosis-specific DMC1 stimulatory effect on DMC1-mediated D-loop reaction. Mechanistic...
The XRCC1-DNA ligase IIIα complex (XL) is critical for DNA single-strand break repair, a key target PARP inhibitors in cancer cells deficient homologous recombination. Here, we combined biophysical approaches to gain insights into the shape and conformational flexibility of XL as well XRCC1 (LigIIIα) alone. Structurally-guided mutational analyses based on crystal structure human BRCT-BRCT heterodimer identified network salt bridges that together with N-terminal extension C-terminal BRCT...
Abstract Senataxin (SETX), a putative RNA-DNA helicase, is recruited to transcription pause sites via the tumor suppressor BRCA1. Here, we define mechanism by which SETX-BRCA1 resolves transcription-associated R-loops prevent deleterious outcomes. Specifically, show that SETX unwinds R-loops, and complex of BRCA1 its obligatory partner BARD1 binds stimulates R-loop unwinding SETX. Importantly, BRCA1-BARD1 alleviates inhibitory effect RAD52 on SETX-mediated unwinding. We also demonstrate...
Activating signal co-integrator complex 1 (ASCC1) acts with ASCC-ALKBH3 in alkylation damage responses. ASCC1 uniquely combines two evolutionarily ancient domains: nucleotide-binding K-Homology (KH) (associated regulating splicing, transcriptional, and translation) two-histidine phosphodiesterase (PDE) hydrolysis of cyclic nucleotide phosphate bonds). Germline mutations link loss function to spinal muscular atrophy congenital bone fractures 2 (SMABF2). Herein analysis The Cancer Genome Atlas...