DNA polymerase κ suppresses inflammation and inflammation-induced mutagenesis and carcinogenic potential in the colon of mice

• Published in: Genes and environment Vol. 45; no. 1; p. 15
• Main Authors: Hakura, Atsushi, Sui, Hajime, Seki, Yuki, Sonoda, Jiro, Yoshida, Yusaku, Takagi, Hisayoshi, Yokose, Shigeo, Matsuda, Tomonari, Asakura, Shoji, Nohmi, Takehiko
• Format: Journal Article
• Language: English
• Published: England BioMed Central 22-04-2023; BMC
• Subjects: Cancer; Carcinogens; Cell growth; Cell proliferation; Chromosomes; Chronic inflammation; Colitis; Colon; Coronary vessels; Cytoplasm; Deoxyribonucleic acid; Dextran; Dextran sulfate; Dextrans; DNA; DNA biosynthesis; DNA damage; DNA polymerase; DNA polymerase κ; DNA repair; DNA-directed DNA polymerase; Drinking water; Dysplasia; Experiments; Females; Health risks; Histopathology; In vivo mutation; Inflammation; Inflammatory bowel disease; Large intestine; Mutagenesis; Mutation; Reporter gene; Translesion DNA synthesis; Tumorigenesis; β-Catenin; Japan; In vivo mutation; Dysplasia; DNA polymerase κ; Chronic inflammation; DNA damage; Translesion DNA synthesis; Colitis
• ISSN: 1880-7046; 1880-7062; 1880-7062
• DOI: 10.1186/s41021-023-00272-7

Chronic inflammation induces DNA damage and promotes cell proliferation, thereby increasing the risk of cancer. DNA polymerase κ (Pol κ), involved in translesion DNA synthesis, counteracts mutagenesis induced by inflammation in the colon of mice. In the present study, we examined whether Pol κ suppressed inflammation-induced colon tumorigenesis by treating inactivated Polk knock-in (Polk
) mice with dextran sulfate sodium (DSS), an inducer of colon inflammation.
Male and female Polk
and Polk
mice were administered 2% DSS in drinking water for six consecutive days, succeeded via a recovery period of 16 days, followed by 2% DSS for another two days. DSS treatment strongly induced colitis, and the severity of colitis was higher in Polk
mice than in Polk
mice. The mice were sacrificed after 19 weeks from the initiation of the first DSS treatment and subjected to pathological examination and mutation analysis. DSS treatment induced colonic dysplasia, and the multiplicity of dysplasia was higher in Polk
mice than in Polk
mice. Some of the dysplasias in Polk
mice exhibited β-catenin-stained nucleus and/or cytoplasm. Mutation frequencies in the gpt reporter gene were increased by DSS treatment in Polk
mice, and were higher than those in Polk
mice.
Pol κ suppresses inflammation and inflammation-induced dysplasia as well as inflammation-induced mutagenesis. The possible mechanisms by which Pol κ suppresses colitis- and colitis-induced dysplasia are discussed.