Biology Reference
In-Depth Information
Oxidized Base Damage and
Single-Strand Break Repair in
Mammalian Genomes: Role of
Disordered Regions and
Posttranslational
Modifications in Early
Enzymes
Muralidhar L. Hegde,
*
Tadahide Izumi,
{
and
Sankar Mitra
*
*Department of Biochemistry and
Molecular Biology, University of Texas
Medical Branch, Galveston, Texas, USA
{
Graduate Center for Toxicology, University
of Kentucky, Lexington, Kentucky, USA
I. Oxidative DNA Damage and Its Repair in Mammalian Cells. . . . . . . . . . . . . . . . . . . .
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A. BER of Oxidized Bases and AP sites in Mammalian Genomes . . . . . . . . . . . . .
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B. DG: The BER-initiating Enzyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. SSBR: A DG-independent Variant of BER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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D. BER/SSBR in Mammalian Mitochondria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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II. Complexity and Sub-pathways of BER/SSBR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. Preferred and Backup Sub-pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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B. Role of Noncanonical Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. Repair Interactome: Preformed Complexes Versus Sequential
Recruitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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III. Nonconserved Terminal Extensions in Mammalian Early BER Proteins . . . . .
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A. Functions of Disordered Terminal Extensions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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IV. Posttranslational Modifications in Early BER Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. Acetylation and Phosphorylation Modulate Repair Activity. . . . . . . . . . . . . . . . . .
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B. Ubiquitylation and BER Protein Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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V. BER/SSBR Deficiency in Human Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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B. Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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C. BER/SSBR as Cancer Therapeutic Targets: Are We at a Crossroad? . . . . .
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VI. Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Oxidative genome damage induced by reactive oxygen species includes
oxidized bases, abasic (AP) sites, and single-strand breaks, all of which are
repaired via the evolutionarily conserved base excision repair/single-strand
break repair (BER/SSBR) pathway. BER/SSBR in mammalian cells is complex,
