Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation

Kousho Wakae; Tomoaki Nishiyama; Satoru Kondo; Takashi Izuka; Lusheng Que; Cong Chen; Kina Kase; Kouichi Kitamura; Md Mohiuddin; Zhe Wang; Md Monjurul Ahasan; Mitsuhiro Nakamura; Hiroshi Fujiwara; Tomokazu Yoshizaki; Kazuyoshi Hosomochi; Atsushi Tajima; Tomomi Nakahara; Tohru Kiyono; Masamichi Muramatsu

doi:10.1038/s41598-018-27930-z

Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation

Kousho Wakae^*, Tomoaki Nishiyama, Satoru Kondo, Takashi Izuka, Lusheng Que, Cong Chen, Kina Kase, Kouichi Kitamura, Md Mohiuddin, Zhe Wang, Md Monjurul Ahasan, Mitsuhiro Nakamura, Hiroshi Fujiwara, Tomokazu Yoshizaki, Kazuyoshi Hosomochi, Atsushi Tajima, Tomomi Nakahara, Tohru Kiyono, Masamichi Muramatsu

^*Corresponding author for this work

Program of Biological Science

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Abstract

Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed.

Original language	English
Article number	9745
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-27930-z
State	Published - 2018/12/01

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Wakae, K., Nishiyama, T., Kondo, S., Izuka, T., Que, L., Chen, C., Kase, K., Kitamura, K., Mohiuddin, M., Wang, Z., Ahasan, M. M., Nakamura, M., Fujiwara, H., Yoshizaki, T., Hosomochi, K., Tajima, A., Nakahara, T., Kiyono, T., & Muramatsu, M. (2018). Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation. Scientific Reports, 8(1), Article 9745. https://doi.org/10.1038/s41598-018-27930-z

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title = "Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation",

abstract = "Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed.",

author = "Kousho Wakae and Tomoaki Nishiyama and Satoru Kondo and Takashi Izuka and Lusheng Que and Cong Chen and Kina Kase and Kouichi Kitamura and Md Mohiuddin and Zhe Wang and Ahasan, {Md Monjurul} and Mitsuhiro Nakamura and Hiroshi Fujiwara and Tomokazu Yoshizaki and Kazuyoshi Hosomochi and Atsushi Tajima and Tomomi Nakahara and Tohru Kiyono and Masamichi Muramatsu",

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doi = "10.1038/s41598-018-27930-z",

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Wakae, K, Nishiyama, T, Kondo, S, Izuka, T, Que, L, Chen, C, Kase, K, Kitamura, K, Mohiuddin, M, Wang, Z, Ahasan, MM, Nakamura, M, Fujiwara, H, Yoshizaki, T, Hosomochi, K, Tajima, A, Nakahara, T, Kiyono, T & Muramatsu, M 2018, 'Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation', Scientific Reports, vol. 8, no. 1, 9745. https://doi.org/10.1038/s41598-018-27930-z

TY - JOUR

T1 - Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation

AU - Wakae, Kousho

AU - Nishiyama, Tomoaki

AU - Kondo, Satoru

AU - Izuka, Takashi

AU - Que, Lusheng

AU - Chen, Cong

AU - Kase, Kina

AU - Kitamura, Kouichi

AU - Mohiuddin, Md

AU - Wang, Zhe

AU - Ahasan, Md Monjurul

AU - Nakamura, Mitsuhiro

AU - Fujiwara, Hiroshi

AU - Yoshizaki, Tomokazu

AU - Hosomochi, Kazuyoshi

AU - Tajima, Atsushi

AU - Nakahara, Tomomi

AU - Kiyono, Tohru

AU - Muramatsu, Masamichi

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed.

AB - Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed.

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U2 - 10.1038/s41598-018-27930-z

DO - 10.1038/s41598-018-27930-z

M3 - 学術論文

C2 - 29950685

AN - SCOPUS:85049140568

SN - 2045-2322

VL - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 9745

ER -

Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation

Abstract

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