title: Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication.
abstract: The genetic information encoded in genomes must be faithfully replicated and transmitted to daughter cells. The recent discovery of consecutive DNA conversions by TET family proteins of 5-methylcytosine into 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (5caC) suggests these modified cytosines act as DNA lesions, which could threaten genome integrity. Here, we have shown that although 5caC pairs with guanine during DNA replication in vitro, G·5caC pairs stimulated DNA polymerase exonuclease activity and were recognized by the mismatch repair (MMR) proteins. Knockdown of thymine DNA glycosylase increased 5caC in genome, affected cell proliferation via MMR, indicating MMR is a novel reader for 5caC. These results suggest the epigenetic modification products of 5caC behave as DNA lesions.
authors.affiliation: Graduate School of Engineering Science, Osaka University Graduate School of Engineering Science, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531 Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shibutani
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ito
authors.affiliation: Graduate School of Engineering Science, Osaka University Graduate School of Engineering Science, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531 Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Toda
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Kanao
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Collins
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Marika
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Urabe
authors.affiliation: Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: 1] Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan [2] Department of Toxicogenomics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Masuda
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Chikahide
authors.initials: C
authors.lastname: Masutani
authors.affiliation: Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Hanaoka
authors.affiliation: Graduate School of Engineering Science, Osaka University Graduate School of Engineering Science, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531 Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Iwai
authors.affiliation: Graduate School of Engineering Science, Osaka University Graduate School of Engineering Science, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531 Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Kuraoka
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D020029:Base Pairing / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D006147:Guanine / Q000378:metabolism*; D006801:Humans; D044502:Thymine DNA Glycosylase / Q000378:metabolism
chemical_list: C560974:5-carboxylcytosine; C560973:5-formylcytosine; C011865:5-hydroxymethylcytosine; D006147:Guanine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D044502:Thymine DNA Glycosylase