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  1. Article: DNA Polymerase β in the Context of Cancer.

    Sawyer, Danielle L / Sweasy, Joann B

    Critical reviews in oncogenesis

    2023  Volume 27, Issue 2, Page(s) 17–33

    Abstract: DNA polymerase beta (Pol β) is a 39 kD vertebrate polymerase that lacks proofreading ability, yet still maintains a moderate fidelity of DNA synthesis. Pol β is a key enzyme that functions in the base excision repair and non-homologous end joining ... ...

    Abstract DNA polymerase beta (Pol β) is a 39 kD vertebrate polymerase that lacks proofreading ability, yet still maintains a moderate fidelity of DNA synthesis. Pol β is a key enzyme that functions in the base excision repair and non-homologous end joining pathways of DNA repair. Mechanisms of fidelity for Pol β are still being elucidated but are likely to involve dynamic conformational motions of the enzyme upon its binding to DNA and deoxynucleoside triphosphates. Recent studies have linked germline and somatic variants of Pol β with cancer and autoimmunity. These variants induce genomic instability by a number of mechanisms, including error-prone DNA synthesis and accumulation of single nucleotide gaps that lead to replication stress. Here, we review the structure and function of Pol β, and we provide insights into how structural changes in Pol β variants may contribute to genomic instability, mutagenesis, disease, cancer development, and impacts on treatment outcomes.
    MeSH term(s) Humans ; DNA Polymerase beta/genetics ; DNA Polymerase beta/chemistry ; DNA Polymerase beta/metabolism ; DNA Replication/genetics ; DNA/genetics ; DNA Repair/genetics ; Genomic Instability ; Neoplasms/genetics
    Chemical Substances DNA Polymerase beta (EC 2.7.7.7) ; DNA (9007-49-2)
    Language English
    Publishing date 2023-02-03
    Publishing country United States
    Document type Review ; Journal Article
    ZDB-ID 1036388-9
    ISSN 0893-9675
    ISSN 0893-9675
    DOI 10.1615/CritRevOncog.2022043477
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  2. Article ; Online: Evelyn M. Witkin (1921-2023).

    Sweasy, Joann B / Hanawalt, Philip C

    Science (New York, N.Y.)

    2023  Volume 381, Issue 6662, Page(s) 1052

    Abstract: Pioneer of cell mutagenesis and DNA repair research. ...

    Abstract Pioneer of cell mutagenesis and DNA repair research.
    MeSH term(s) DNA Repair ; Genetics/history ; Mutagenesis ; United States
    Language English
    Publishing date 2023-09-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.adk1028
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  3. Article ; Online: Functional roles and cancer variants of the bifunctional glycosylase NEIL2.

    Hua, Anh B / Sweasy, Joann B

    Environmental and molecular mutagenesis

    2023  Volume 65 Suppl 1, Page(s) 40–56

    Abstract: Over 70,000 DNA lesions occur in the cell every day, and the inability to properly repair them can lead to mutations and destabilize the genome, resulting in carcinogenesis. The base excision repair (BER) pathway is critical for maintaining genomic ... ...

    Abstract Over 70,000 DNA lesions occur in the cell every day, and the inability to properly repair them can lead to mutations and destabilize the genome, resulting in carcinogenesis. The base excision repair (BER) pathway is critical for maintaining genomic integrity by repairing small base lesions, abasic sites and single-stranded breaks. Monofunctional and bifunctional glycosylases initiate the first step of BER by recognizing and excising specific base lesions, followed by DNA end processing, gap filling, and finally nick sealing. The Nei-like 2 (NEIL2) enzyme is a critical bifunctional DNA glycosylase in BER that preferentially excises cytosine oxidation products and abasic sites from single-stranded, double-stranded, and bubble-structured DNA. NEIL2 has been implicated to have important roles in several cellular functions, including genome maintenance, participation in active demethylation, and modulation of the immune response. Several germline and somatic variants of NEIL2 with altered expression and enzymatic activity have been reported in the literature linking them to cancers. In this review, we provide an overview of NEIL2 cellular functions and summarize current findings on NEIL2 variants and their relationship to cancer.
    MeSH term(s) Humans ; DNA Glycosylases/genetics ; DNA Glycosylases/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; DNA ; Neoplasms/genetics
    Chemical Substances DNA Glycosylases (EC 3.2.2.-) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; DNA (9007-49-2) ; NEIL2 protein, human (EC 4.2.99.18)
    Language English
    Publishing date 2023-06-26
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 639145-x
    ISSN 1098-2280 ; 0893-6692
    ISSN (online) 1098-2280
    ISSN 0893-6692
    DOI 10.1002/em.22555
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  4. Article ; Online: DNA polymerase κ: Friend or foe?

    Sweasy, Joann B

    Science signaling

    2020  Volume 13, Issue 629

    Abstract: In this issue ... ...

    Abstract In this issue of
    MeSH term(s) DNA Damage ; DNA-Directed DNA Polymerase/genetics ; Drug Resistance
    Chemical Substances DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2020-04-28
    Publishing country United States
    Document type Journal Article ; Review ; Comment
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.abb2934
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  5. Article ; Online: Timing Is Everything: Misincorporation of 8oxodG during Mitosis Is Lethal.

    Alnajjar, Khadijeh / Sweasy, Joann B

    Cancer research

    2020  Volume 80, Issue 17, Page(s) 3459–3460

    Abstract: Exploiting universal cancer vulnerabilities has been used as an approach for developing targeted therapies. In this issue ... ...

    Abstract Exploiting universal cancer vulnerabilities has been used as an approach for developing targeted therapies. In this issue of
    MeSH term(s) 8-Hydroxy-2'-Deoxyguanosine ; Genomics ; Humans ; Mitosis ; Neoplasms ; Reactive Oxygen Species
    Chemical Substances Reactive Oxygen Species ; 8-Hydroxy-2'-Deoxyguanosine (88847-89-6)
    Language English
    Publishing date 2020-08-30
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-1904
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  6. Article ; Online: Temporal coordination of the transcription factor response to H

    Jose, Elizabeth / March-Steinman, Woody / Wilson, Bryce A / Shanks, Lisa / Parkinson, Chance / Alvarado-Cruz, Isabel / Sweasy, Joann B / Paek, Andrew L

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 3440

    Abstract: Oxidative stress from excess ... ...

    Abstract Oxidative stress from excess H
    MeSH term(s) Hydrogen Peroxide/metabolism ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/drug effects ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Humans ; Peroxiredoxins/metabolism ; Peroxiredoxins/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/genetics ; NF-E2-Related Factor 2/metabolism ; NF-E2-Related Factor 2/genetics ; NF-kappa B/metabolism ; Forkhead Box Protein O1/metabolism ; Forkhead Box Protein O1/genetics ; NFATC Transcription Factors/metabolism ; Glucose Oxidase/metabolism ; Animals
    Chemical Substances Hydrogen Peroxide (BBX060AN9V) ; Transcription Factors ; Peroxiredoxins (EC 1.11.1.15) ; Tumor Suppressor Protein p53 ; NF-E2-Related Factor 2 ; NF-kappa B ; Forkhead Box Protein O1 ; NFATC Transcription Factors ; Glucose Oxidase (EC 1.1.3.4)
    Language English
    Publishing date 2024-04-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-47837-w
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  7. Article ; Online: A new perspective on oxidation of DNA repair proteins and cancer.

    Alnajjar, Khadijeh S / Sweasy, Joann B

    DNA repair

    2019  Volume 76, Page(s) 60–69

    Abstract: Reactive oxygen and nitrogen species (RONS) are formed as byproducts of many endogenous cellular processes, in response to infections, and upon exposure to various environmental factors. An increase in RONS can saturate the antioxidation system and leads ...

    Abstract Reactive oxygen and nitrogen species (RONS) are formed as byproducts of many endogenous cellular processes, in response to infections, and upon exposure to various environmental factors. An increase in RONS can saturate the antioxidation system and leads to oxidative stress. Consequently, macromolecules are targeted for oxidative modifications, including DNA and protein. The oxidation of DNA, which leads to base modification and formation of abasic sites along with single and double strand breaks, has been extensively investigated. Protein oxidation is often neglected and is only recently being recognized as an important regulatory mechanism of various DNA repair proteins. This is a review of the current state of research on the regulation of DNA repair by protein oxidation with emphasis on the correlation between inflammation and cancer.
    MeSH term(s) Animals ; DNA Breaks, Double-Stranded ; DNA Repair ; Humans ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/metabolism ; O(6)-Methylguanine-DNA Methyltransferase/metabolism ; Oxidation-Reduction ; Proteins/metabolism
    Chemical Substances Proteins ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63)
    Language English
    Publishing date 2019-02-18
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2019.02.006
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  8. Article ; Online: NTHL1 in genomic integrity, aging and cancer.

    Das, Lipsa / Quintana, Victoria G / Sweasy, Joann B

    DNA repair

    2020  Volume 93, Page(s) 102920

    Abstract: Efficient DNA repair is essential to maintain genomic integrity. An average of 30,000 base lesions per cell are removed daily by the DNA glycosylases of the base excision repair machinery. With the advent of whole genome sequencing, many germline ... ...

    Abstract Efficient DNA repair is essential to maintain genomic integrity. An average of 30,000 base lesions per cell are removed daily by the DNA glycosylases of the base excision repair machinery. With the advent of whole genome sequencing, many germline mutations in these DNA glycosylases have been identified and associated with various diseases, including cancer. In this graphical review, we discuss the function of the NTHL1 DNA glycosylase and how genomic mutations and altered function of this protein contributes to cancer and aging. We highlight its role in a rare tumor syndrome, NTHL1-associated polyposis (NAP), and summarize various other polymorphisms in NTHL1 that can induce early hallmarks of cancer, including genomic instability and cellular transformation.
    MeSH term(s) Aging/genetics ; Aging/metabolism ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/genetics ; DNA/metabolism ; DNA Glycosylases/metabolism ; DNA Repair ; Deoxyribonuclease (Pyrimidine Dimer)/genetics ; Deoxyribonuclease (Pyrimidine Dimer)/metabolism ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Intestinal Polyposis/enzymology ; Intestinal Polyposis/genetics ; Polymorphism, Genetic
    Chemical Substances DNA (9007-49-2) ; Deoxyribonuclease (Pyrimidine Dimer) (EC 3.1.25.1) ; NTHL1 protein, human (EC 3.1.25.1) ; DNA Glycosylases (EC 3.2.2.-)
    Language English
    Publishing date 2020-10-21
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2020.102920
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  9. Article ; Online: The role of cysteines in the structure and function of OGG1.

    Wang, Katarina / Maayah, Marah / Sweasy, Joann B / Alnajjar, Khadijeh S

    The Journal of biological chemistry

    2020  Volume 296, Page(s) 100093

    Abstract: 8-Oxoguanine glycosylase (OGG1) is a base excision repair enzyme responsible for the recognition and removal of 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates the transcription of ... ...

    Abstract 8-Oxoguanine glycosylase (OGG1) is a base excision repair enzyme responsible for the recognition and removal of 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates the transcription of various oxidative stress-response genes. In addition to targeting DNA, oxidative stress can affect proteins like OGG1 itself, specifically at cysteine residues. Previous work has shown that the function of OGG1 is sensitive to oxidants, with the cysteine residues of OGG1 being the most likely site of oxidation. Due to the integral role of OGG1 in maintaining cellular homeostasis under oxidative stress, it is important to understand the effect of oxidants on OGG1 and the role of cysteines in its structure and function. In this study, we investigate the role of the cysteine residues in the function of OGG1 by mutating and characterizing each cysteine residue. Our results indicate that the cysteines in OGG1 fall into four functional categories: those that are necessary for (1) glycosylase activity (C146 and C255), (2) lyase activity (C140S, C163, C241, and C253), and (3) structural stability (C253) and (4) those with no known function (C28 and C75). These results suggest that under conditions of oxidative stress, cysteine can be targeted for modifications, thus altering the response of OGG1 and affecting its downstream cellular functions.
    MeSH term(s) Cysteine/chemistry ; Cysteine/metabolism ; DNA Glycosylases/chemistry ; DNA Glycosylases/metabolism ; DNA Repair/physiology ; Electrophoretic Mobility Shift Assay ; Oxidation-Reduction ; Oxidative Stress/physiology
    Chemical Substances DNA Glycosylases (EC 3.2.2.-) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2020-11-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.016126
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    Uc I Zs.108: Show issues Location:
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  10. Article ; Online: Polymorphic variant Asp239Tyr of human DNA glycosylase NTHL1 is inactive for removal of a variety of oxidatively-induced DNA base lesions from genomic DNA.

    Kant, Melis / Quintana, Victoria / Coskun, Erdem / Jaruga, Pawel / Lloyd, R Stephen / Sweasy, Joann B / Dizdaroglu, Miral

    DNA repair

    2022  Volume 117, Page(s) 103372

    Abstract: Base excision repair is the major pathway for the repair of oxidatively-induced DNA damage, with DNA glycosylases removing modified bases in the first step. Human NTHL1 is specific for excision of several pyrimidine- and purine-derived lesions from DNA, ... ...

    Abstract Base excision repair is the major pathway for the repair of oxidatively-induced DNA damage, with DNA glycosylases removing modified bases in the first step. Human NTHL1 is specific for excision of several pyrimidine- and purine-derived lesions from DNA, with loss of function NTHL1 showing a predisposition to carcinogenesis. A rare single nucleotide polymorphism of the Nthl1 gene leading to the substitution of Asp239 with Tyr within the active site, occurs within global populations. In this work, we overexpressed and purified the variant NTHL1-Asp239Tyr (NTHL1-D239Y) and determined the substrate specificity of this variant relative to wild-type NTHL1 using gas chromatography-tandem mass spectrometry with isotope-dilution, and oxidatively-damaged genomic DNA containing multiple pyrimidine- and purine-derived lesions. Wild-type NTHL1 excised seven DNA base lesions with different efficiencies, whereas NTHL1-D239Y exhibited no glycosylase activity for any of these lesions. We also measured the activities of human glycosylases OGG1 and NEIL1, and E. coli glycosylases Nth and Fpg under identical experimental conditions. Different substrate specificities among these DNA glycosylases were observed. When mixed with NTHL1-D239Y, the activity of NTHL1 was not reduced, indicating no substrate binding competition. These results and the inactivity of the variant D239Y toward the major oxidatively-induced DNA lesions points to the importance of the understanding of this variant's role in carcinogenesis and the potential of individual susceptibility to cancer in individuals carrying this variant.
    MeSH term(s) Carcinogenesis ; DNA/metabolism ; DNA Damage ; DNA Glycosylases/metabolism ; DNA Repair ; Deoxyribonuclease (Pyrimidine Dimer)/genetics ; Deoxyribonuclease (Pyrimidine Dimer)/metabolism ; Escherichia coli/genetics ; Genomics ; Humans ; Purines ; Pyrimidines/metabolism ; Substrate Specificity
    Chemical Substances Purines ; Pyrimidines ; DNA (9007-49-2) ; Deoxyribonuclease (Pyrimidine Dimer) (EC 3.1.25.1) ; NTHL1 protein, human (EC 3.1.25.1) ; DNA Glycosylases (EC 3.2.2.-) ; NEIL1 protein, human (EC 3.2.2.-)
    Language English
    Publishing date 2022-07-16
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2022.103372
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