A5090703875- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Carcinogens and Genotoxicity Assessment
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- RNA Interference and Gene Delivery
- Polyomavirus and related diseases
- Tuberous Sclerosis Complex Research
- Advanced biosensing and bioanalysis techniques
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Genomics, phytochemicals, and oxidative stress
- Indoor Air Quality and Microbial Exposure
- Genetic and Kidney Cyst Diseases
- Long-Term Effects of COVID-19
- Smoking Behavior and Cessation
- Musculoskeletal pain and rehabilitation
- Animal Genetics and Reproduction
- Biochemical and Molecular Research
- Immunotherapy and Immune Responses
- Mitochondrial Function and Pathology
- Toxic Organic Pollutants Impact
Lawrence Berkeley National Laboratory
2015-2024
Dhaka Medical College and Hospital
2023
Okayama University
1993-2005
University of California, Berkeley
2004
The human endonuclease III (hNTH1), a homolog of the <i>Escherichia coli</i> enzyme (Nth), is DNA glycosylase with abasic (apurinic/apyrimidinic (AP)) lyase activity and specifically cleaves oxidatively damaged pyrimidines in DNA. Its cDNA was cloned, full-length (304 amino acid residues) expressed as glutathione <i>S</i>-transferase fusion polypeptide <i>E. coli</i>. Purified wild-type protein two additional residues truncated deletion 22 at NH<sub>2</sub> terminus were equally active had...
Abstract DNA double-strand breaks (DSBs) leading to loss of nucleotides in the transcribed region can be lethal. Classical non-homologous end-joining (C-NHEJ) is dominant pathway for DSB repair (DSBR) adult mammalian cells. Here we report that during such DSBR, C-NHEJ proteins form a multiprotein complex with RNA polymerase II and preferentially associate genes after induction. Depletion factors significantly abrogates DSBR but not non-transcribed genes. We hypothesized nascent serve as...
Exposure to thirdhand smoke (THS) is a newly described health risk. Evidence supports its widespread presence in indoor environments. However, genotoxic potential, critical aspect risk assessment, virtually untested. An important characteristic of THS ability undergo chemical transformations during aging periods, as demonstrated recent study showing that sorbed nicotine reacts with the pollutant nitrous acid (HONO) form tobacco-specific nitrosamines (TSNAs) such...
Abstract DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, FEN1 mutations arise in multiple cancers. precisely cleaves single-stranded (ss) 5′-flaps one nucleotide into duplex (ds) DNA. Yet, how selects but does not incise the ss 5′-flap was enigmatic. Here we combine crystallographic, biochemical genetic analyses to show that two dsDNA binding sites set 5′polarity reveal unexpected control of phosphodiester backbone by electrostatic interactions....
Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine biological role of these DGs, null animal models have been generated. Here, we report generation and characterization mice lacking Neil2 (Nei-like 2). As in deficient each other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, NEIL3), Neil2-null show no overt phenotype....
As part of the Nucleotide Excision Repair (NER) process, endonuclease XPG is involved in repair helix-distorting DNA lesions, but protein has also been implicated several other systems, complicating genotype-phenotype relationship patients. Defects can cause either cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with severe neurodevelopmental disorder Cockayne Syndrome (CS), infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic...
Third hand smoke (THS) is the accumulation of second (SHS) toxins on surfaces in homes, cars, clothing and hair smokers. It known that 88M US nonsmokers ≥3 years old living homes smokers are exposed to THS toxicants show blood cotinine levels ≥0.05 ng/ml, indicating circulating their circulatory systems. The goal present study investigate mechanisms by which causes impaired wound healing. We mice under conditions mimic exposure humans display delayed closure, collagen deposition, altered...
Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and pathway coordinator structure-specific endonuclease nucleotide excision repair (NER). Different mutations the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma (XP-G) or fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address enigmatic structural mechanism for these differing disease phenotypes XPG’s role DDRs, here we...
Tobacco-specific nitrosamines (TSNAs) are emitted during smoking and form indoors by nitrosation of nicotine. Two them,
Human positive cofactor 4 (PC4) is a transcriptional coactivator with highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as suppressor the oxidative mutator phenotype Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA activity. Saccharomyces cerevisiae mutants lacking their ortholog Sub1 are sensitive to hydrogen peroxide exhibit spontaneous peroxide-induced hypermutability. expression suppresses sensitivity...
Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, the frontline for repairing potentially mutagenic base damage. The NTHL1 glycosylase, excises damage caused reactive oxygen species, thought to be a tumor suppressor. However, in addition loss-of-function mutations, our analysis of cancer genomic datasets reveals that frequently undergoes amplification or upregulation some cancers. Whether overexpression could contribute phenotypes has not yet been explored. To...
Significance Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease with no effective treatments. SCA3 etiologically linked to an abnormal polyglutamine (polyQ) tract at the C terminus of Ataxin-3 (ATXN3). How this polyQ stretch causes pathology remains elusive. Here we provide evidence that wild-type ATXN3 plays important role in error-free repair DNA double-strand breaks transcribed genes. In contrast, mutant blocks activity end-processing enzyme, polynucleotide kinase...
Secondhand smoke (SHS) is a confirmed lung carcinogen that introduces thousands of toxic chemicals into the lungs. SHS contains have been implicated in causing oxidative DNA damage airway epithelium. Although repair considered key defensive mechanism against various environmental attacks, such as cigarette smoking, associations individual enzymes with susceptibility to cancer are largely unknown. This study investigated role NEIL2, glycosylase excising base lesions, human cells treated...
Exposure to thirdhand smoke (THS) is a recently described health concern that arises in many indoor environments. However, the carcinogenic potential of THS, critical consideration risk assessment, remains untested. Here we investigated effects short-term early exposure THS on lung carcinogenesis A/J mice. Forty weeks after from 4 7 age, mice had increased incidence adenocarcinoma, tumor size and, multiplicity, compared with controls. In vitro studies using cultured human cancer cells showed...
Abstract Mammalian polynucleotide kinase 3′-phosphatase (PNKP), a DNA end-processing enzyme with and 5′-kinase activities, is involved in multiple repair pathways, including base excision (BER), single-strand break (SSBR), double-strand (DSBR). However, little known as to how PNKP functions such diverse processes. Here we report that acetylated at K142 (AcK142) by p300 constitutively but K226 (AcK226) CBP, only after DSB induction. Co-immunoprecipitation analysis using AcK142 or AcK226...
Polynucleotide kinase 3'-phosphatase (PNKP), an essential DNA end-processing enzyme in mammals with and 5'-kinase activities, plays a pivotal role multiple repair pathways. Its functional deficiency has been etiologically linked to various neurological disorders. Recent reports have shown that mutation at conserved glutamine (Gln) PNKP leads late-onset ataxia oculomotor apraxia type 4 (AOA4) humans embryonic lethality pigs. However, the molecular mechanism underlying such phenotypes remains...
Abstract SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces genome activates DNA pathways. To test whether the compromised repair capacity individuals modulates severity infection, we analyze gene expression publicly available patient datasets observe a lower level glycosylase NEIL2 lungs severely infected patients. This observation levels is further validated patients, hamsters...