5BPC

DNA polymerase beta ternary complex with a templating 5ClC and incoming dATP analog

Summary for 5BPC

• Entry DOI: 10.2210/pdb5bpc/pdb
• Descriptor: DNA polymerase beta, DNA (5'-D(P*GP*TP*CP*GP*G)-3'), DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*C)-3'), ... (8 entities in total)
• Functional Keywords: transferase, lyase/dna, ligase-dna complex, ligase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 48434.24

Authors

Freudenthal, B.D.,Wilson, S.H. (deposition date: 2015-05-28, release date: 2015-08-19, Last modification date: 2024-03-06)

Primary citation

Fedeles, B.I.,Freudenthal, B.D.,Yau, E.,Singh, V.,Chang, S.C.,Li, D.,Delaney, J.C.,Wilson, S.H.,Essigmann, J.M.
Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer.
Proc.Natl.Acad.Sci.USA, 112:E4571-E4580, 2015

PubMed Abstract: During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.

PubMed: 26243878
DOI: 10.1073/pnas.1507709112

Experimental method

X-RAY DIFFRACTION (2 Å)