A myriad of lesions in DNA are caused by ubiquitous environmental and endogenous genotoxic agents. These DNA lesions can interfere with normal DNA metabolism including DNA replication, eventually resulting in mutations that lead to carcinogenesis, senescence and/or cell death. To cope with DNA damages, cells have multiple mechanisms such as Cell Cycle Checkpoint, DNA Repair and DNA Damage Tolerance which includes TransLesion Synthesis (TLS). Dozens of inherited diseases are known or suspected to be caused by defects of these mechanisms. This department aims to elucidate molecular bases of cellular DNA damage responses relating to the human disorders. We have identified human DNA polymerase eta (Polη) as the responsible gene product of XPV (xeroderma pigmentosum variant) and shown that Polη catalyzes efficient and accurate TLS past unrepaired UV-induced pyrimidine dimers, therefore prevents UV-induced carcinogenesis.
Major current projects are as follows:
Identification and/or analysis of:
- Regulatory mechanisms of TLS
- Unidentified DNA damage tolerance pathways
- Physiological relevance of DNA damage tolerance
- Crosstalk between multiple DNA damage response mechanisms
- Therapeutic targets for genome instability diseases
Recent publications (2010.4-2015.3)
- Kanao R, Yokoi M, Ohkumo T, Sakurai Y, Dotsu K, Kura S, Nakatsu Y, Tsuzuki T, Masutani C, Hanaoka F: UV-induced mutagenesis in epidermal cells of mice defective in DNA polymerase η and/or ι. DNA Repair 29: 139-146, 2015.
- Takahata C, Masuda Y, Takedachi A, Tanaka K, Iwai S, Kuraoka I: Repair synthesis step involving ERCC1-XPF participates in DNA repair of the Top1-DNA damage complex. Carcinogenesis 36: 841-851, 2015
- Niimi A, Hopkins SR, Downs JA, Masutani C: The BAH domain of BAF180 is required for PCNA ubiquitination. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 779: 16-23, 2015.
- Masuda Y, Kanao R, Kaji K, Ohmori H, Hanaoka F, Masudani C. Different types of interaction between PCNA and PIP boxes contribute to distinct cellular functions of Y-family DNA polymerases. Nucleic Acids Res. doi: 10.1093/nar/gkv712
- Yamamoto J, Oyama T, Kunishi T, Masutani C, Hanaoka F, Iwai S: A cyclobutane thymine-N4-methylcytosine dimer is resistant to hydrolysis but strongly blocks DNA synthesis. Nucleic Acids Res. 42: 2075-2084, 2014.
- Shibutani T, Ito S, Toda M, Kanao R, Collins LB, Shibata M, Urabe M, Koseki H, Masuda Y, Swenberg JA, Masutani C, Hanaoka F, Iwai S, Kuraoka I: Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication. Sci. Rep. 4: 5220, 2014.
- Cao L, Kawai H, Sasatani M, Iizuka D, Masuda Y, Inaba T, Suzuki K, Ootsuyama A, Umata T, Kamiya K, Suzuki F: A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ -irradiation. PLoS ONE 9: e104279, 2014.
- Kamath-Loeb AS, Balakrishna S, Whittington D, Shen JC, Emond MJ, Okabe T, Masutani C, Hanaoka F, Nishimura S, Loeb LA: Sphingosine: a modulator of human translesion DNA polymerase activity. J. Biol. Chem. 289: 21663-21672, 2014.
- Kanao R, Masuda Y, Deguchi S, Yumoto-Sugimoto M, Hanaoka F, Masutani C: Relevance of Simultaneous Mono-Ubiquitinations of Multiple Units of PCNA Homo-Trimers in DNA Damage Tolerance. PLoS One 10: e0118775, 2015.
- Arichi N, Yamamoto J, Takahata C, Sano E, Masuda Y, Kuraoka I, Iwai S: Strand breakage of a (6-4) photoproduct-containing DNA at neutral pH and its repair by the ERCC1-XPF protein complex. Organic & Biomolecular Chemistry 11: 3526-3534, 2013.
- Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, Masuda Y, Matsuda S, Adachi J, Kobayashi M, Meetei AR, Maehara Y, Yamamoto K, Kamiya K, Matsuura A, Matsuda T, Ikura T, Ishiai M, Takata M: A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Research41: 6930-6941, 2013.
- Yamamoto J, Oyama T, Kunishi T, Masutani C, Hanaoka F, Iwai S: A cyclobutane thymine-N4-methylcytosine dimer is resistant to hydrolysis but strongly blocks DNA synthesis. Nucleic Acids Research: 42(3), 2075-2084, 2014.
- Masuda Y, Suzuki M, Kawai H, Hishiki A, Hashimoto H, Masutani C, Hishida T, Suzuki F, Kamiya K: En bloc transfer of polyubiquitin chains to PCNA in vitro is mediated by two different human E2-E3 pairs. Nucleic Acids Research 40: 10394-10407, 2012.
- Masutani C: Human DNA polymeraseηand its regulatory mechanisms. Genes and Environment 34: 63-69, 2012.
- Masuza Y: In vitro studies of exchanges between replicative and translesion DNA polymerases in the eukaryotic post-replication repair pathway. Genes and Environment 34: 70-76, 2012.
- Pozo FM, Oda T, Sekimoto T, Murakumo Y, Masutani C, Hanaoka F, Yamashita T: Molecular chaperone Hsp90 regulates REV1-mediated mutagenesis. Molecular and Cellular Biology 31: 3396-3409, 2011.
- Yanagihara H, Kobayashi J, Tateishi S, Kato A, Matsuura S, Tauchi H, Yamada K, Takezawa J, Sugasawa K, Masutani C, Hanaoka F, Weemaea CM, Mori T, Zou L, Komatsu K: NBS1 recruits RAD18 via a RAD6-like domain and regulates Polη-dependent translesion DNA synthesis. Molecular Cell 43: 788-797, 2011.
- Masuda Y, Kamiya K: Molecular nature of radiation injury and DNA repair disorders associated with radiosensitivity. International Journal of Hematology 95(3): 239-245, 2012.
- Biertumpfel C, Zhao Y, Kondo Y, Ramon-Maiques S, Gregory M, Lee JY, Masutani C, Lehmann AR, Hanaoka F, Yang W: Structure and mechanism of human DNA polymeraseη. Nature 465: 1044-1048, 2010.
- ashiwagi S, Kuraoka I, Fujiwara Y, Hitomi K, Cheng QJ, Fuss JO, Shin DS, Masutani C, Tainer JA, Hanaoka F, Iwai S: Characterization of a Y-family DNA polymerase eta from the eukaryotic themophile Alvinella pompejana. Journal of Nucleic Acids: pii: 701472, 2010.
- Hirota K, Sonoda E, Kawamoto T, Motegi A, Masutani C, Hanaoka F, Szuts D, Iwai S, Sale JE, Lehmann A, Takeda S: Simultaneous disruption of two DNA polymerases, Polη and Polζ, in avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions. PLoS Genetics 6(10): e1001151, 2010.
- Yamamoto J, Nishiguchi K, Manabe K, Masutani C, Hanaoka F, Iwai S: Photosensitized [2 + 2] cycloaddition of N-acetylated cytosine affords stereoselective formation of cyclobutane pyrimidine dimer. Nucleic Acids Research 39: 1165-1175, 2011.
Other major publications
- McCulloch SD, Kokoska RJ, Masutani C, Iwai S, Hanaoka F, Kunkel TA: Preferential cis-syn thymine dimer bypass by DNA polymerase η occurs with biased fidelity. Nature 428：97-100, 2004.
- Matsuda T, Bebenek K, Masutani, C, Hanaoka, F, and Kunkel, TA: Low fidelity DNA synthesis by human DNA polymerase η. Nature 404: 1011-1013, 2000.
- Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T, Maekawa T, Iwai S, Hanaoka F: Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO Journal 18: 3491-3501, 1999.
- Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, Takio K, Hanaoka F: The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η. Nature 399: 700-704, 1999.
(May 1, 2018)