6CRH

Structure of human DNA polymerase beta complexed with 8-ClG in the template base paired with incoming non-hydrolyzable GTP

Summary for 6CRH

• Entry DOI: 10.2210/pdb6crh/pdb
• Descriptor: DNA polymerase beta, DNA (5'-D(*CP*CP*GP*AP*CP*(CGM)P*TP*CP*GP*CP*AP*TP*CP*AP*GP*C)-3'), DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*A)-3'), ... (8 entities in total)
• Functional Keywords: dna binding protein, transferase, lyase-dna complex, lyase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 48342.11

Authors

Koag, M.-C.,Lee, S. (deposition date: 2018-03-17, release date: 2019-03-20, Last modification date: 2024-03-13)

Primary citation

Kou, Y.,Koag, M.C.,Lee, S.
Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion.
Molecules, 24:-, 2019

PubMed Abstract: Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2'-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase β (polβ) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its and conformers, respectively. Kinetic studies showed that polβ incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between -ClG and -dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between -ClG and -G during DNA synthesis.

PubMed: 31569643
DOI: 10.3390/molecules24193507

Experimental method

X-RAY DIFFRACTION (2.327 Å)