BER

BER
Name	Base excision repair
Caption	Schematic of base excision repair pathway
Organism	Homo sapiens, Escherichia coli, Saccharomyces cerevisiae
Discovery	Thomas Lindahl; Paul Modrich; Aziz Sancar
Genes	OGG1, UNG, NTHL1, APE1, POLB, XRCC1, LIG3, FEN1

BER

Base excision repair is a conserved DNA repair pathway that identifies and removes small, non-helix-distorting base lesions arising from oxidation, deamination, and alkylation. Originating from foundational studies by Thomas Lindahl and contemporaries, the pathway operates across bacteria, archaea, and eukaryotes to maintain genomic integrity in organisms such as Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens. It complements other repair systems including nucleotide excision repair and mismatch repair characterized in work by Paul Modrich and Aziz Sancar.

Overview

Base excision repair initiates with lesion recognition by damage-specific DNA glycosylases (e.g., UNG, OGG1), followed by cleavage of the resulting abasic site by apurinic/apyrimidinic endonucleases (e.g., APE1), gap processing by polymerases (e.g., POLB), and strand sealing by ligases (e.g., LIG3 complexed with XRCC1). The pathway is described in short-patch and long-patch subpathways, distinctions elucidated in biochemical studies from laboratories associated with Lindahl and investigators at institutions such as Cold Spring Harbor Laboratory and the National Institutes of Health. Comparative analyses across taxa (e.g., Escherichia coli vs. Saccharomyces cerevisiae) reveal conserved core steps and taxon-specific accessory proteins.

Molecular Mechanism

Lesion recognition is performed by monofunctional or bifunctional glycosylases; monofunctional enzymes (e.g., UNG) hydrolyze the N-glycosidic bond leaving an abasic site, while bifunctional glycosylases (e.g., NTHL1, OGG1) possess lyase activity that incises the backbone. The resulting abasic or nicked intermediate is processed by APE1 in metazoans or by homologous endonucleases in prokaryotes such as Escherichia coli exonuclease III. Short-patch repair involves single-nucleotide replacement by POLB with concomitant lyase removal of the 5′-deoxyribose phosphate; long-patch repair uses flap generation by strand-displacing polymerases and removal by FEN1 followed by ligation via LIG1 or LIG3 with XRCC1 scaffolding. Structural studies from groups at European Molecular Biology Laboratory and Max Planck Society laboratories have resolved glycosylase–DNA and polymerase–DNA complexes, informing catalysis and substrate specificity.

Enzymes and Protein Components

Key glycosylases include UNG (uracil-DNA glycosylase), OGG1 (8-oxoguanine DNA glycosylase), NTHL1 (endonuclease III-like glycosylase), and lesion-specific enzymes characterized in bacterial systems such as Escherichia coli Uracil-DNA glycosylase. The major endonuclease in humans is APE1, while gap-filling polymerases include POLB and replicative polymerases such as POLδ in long-patch contexts. Strand-displacement and flap cleavage involve FEN1, and final ligation is executed by LIG1 or the LIG3–XRCC1 complex. Accessory factors and scaffolds include chromatin remodelers studied in laboratories at Rockefeller University and coordination factors identified via proteomics at European Bioinformatics Institute.

Biological Roles and Importance

This repair system counters damage from reactive oxygen species produced in mitochondria (studied in Max Planck Institute research), endogenous metabolic byproducts, and exogenous agents such as ionizing radiation (investigated at CERN radiation biology programs) and alkylating chemotherapeutics developed by groups at Eli Lilly and Company and Merck & Co.. In mitochondria, the pathway supports respiratory chain integrity and is linked to aging phenotypes explored in studies by Cynthia Kenyon and teams at Salk Institute. In proliferating tissues, BER preserves transmission fidelity during processes studied in developmental biology centers like Howard Hughes Medical Institute-affiliated labs.

Regulation and Coordination with Other Repair Pathways

Cross-talk occurs between BER and nucleotide excision repair components characterized by investigators at Cold Spring Harbor Laboratory; regulatory integration involves post-translational modifications such as phosphorylation by kinases including ATM and ubiquitination pathways mapped by researchers at Broad Institute. Coordination with mismatch repair proteins studied by Paul Modrich influences processing of repair intermediates during DNA replication; interaction with homologous recombination factors characterized at Institute of Cancer Research modulates responses to complex lesions and replication-blocking gaps. Chromatin context and histone modification landscapes elucidated in work from EMBL-EBI direct accessibility of lesions to BER enzymes.

Clinical Significance and Disease Associations

Deficiencies or mutations in BER components are implicated in cancer predisposition (e.g., somatic and germline alterations in OGG1 and MUTYH linked to colorectal neoplasia characterized by teams at Cambridge University and MD Anderson Cancer Center), neurodegenerative disorders (mutations in NTHL1 and mitochondrial repair factors reported in studies from Karolinska Institutet), and age-associated pathologies examined by researchers at Dana-Farber Cancer Institute. BER capacity influences response to chemotherapeutics such as temozolomide and alkylating agents developed in pharmaceutical programs at GlaxoSmithKline. Targeting BER enzymes has been pursued in drug discovery pipelines at Novartis and Pfizer to sensitize tumors or treat repair-deficient syndromes.

Experimental Methods and Assays

Biochemical assays use glycosylase activity measurements, abasic-site cleavage assays, and gel-based substrate turnover developed in labs at Cold Spring Harbor Laboratory and EMBL. Cellular reporters employ lesion-containing plasmids and reporter cassettes used at institutions like MIT and Stanford University to quantify repair efficiency. Structural characterization relies on X-ray crystallography and cryo-electron microscopy from facilities at Diamond Light Source and European Synchrotron Radiation Facility. Proteomic and genomic approaches include mass spectrometry workflows at Max Planck Institute and genome-wide mapping of repair events using high-throughput sequencing platforms pioneered at Broad Institute.

Category:DNA repair