研究者詳細 - 益谷　央豪

Relevance of Simultaneous Mono-Ubiquitinations of Multiple Units of PCNA Homo-Trimers in DNA Damage Tolerance 査読有り国際誌

Kanao Rie, Masuda Yuji, Deguchi Saori, Yumoto-Sugimoto Mayumi, Hanaoka Fumio, Masutani Chikahide

PLOS ONE 10 巻 ( 2 ) 頁： e0118775 2015年2月

担当区分：最終著者,　責任著者記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS ONE

DNA damage tolerance (DDT) pathways, including translesion synthesis (TLS) and additional unknown mechanisms, enable recovery from replication arrest at DNA lesions. DDT pathways are regulated by post-translational modifications of proliferating cell nuclear antigen (PCNA) at its K164 residue. In particular, mono-ubiquitination by the ubiquitin ligase RAD18 is crucial for Polη-mediated TLS. Although the importance of modifications of PCNA to DDT pathways is well known, the relevance of its homo-trimer form, in which three K164 residues are present in a single ring, remains to be elucidated. Here, we show that multiple units of a PCNA homo-trimer are simultaneously mono-ubiquitinated in vitro and in vivo. RAD18 catalyzed sequential mono-ubiquitinations of multiple units of a PCNA homo-trimer in a reconstituted system. Exogenous PCNA formed hetero-trimers with endogenous PCNA in WI38VA13 cell transformants. When K164R-mutated PCNA was expressed in these cells at levels that depleted endogenous PCNA homo-trimers, multiple modifications of PCNA complexes were reduced and the cells showed defects in DDT after UV irradiation. Notably, ectopic expression of mutant PCNA increased the UV sensitivities of Polη-proficient, Polη-deficient, and REV1-depleted cells, suggesting the disruption of a DDT pathway distinct from the Polη- and REV1-mediated pathways. These results suggest that simultaneous modifications of multiple units of a PCNA homo-trimer are required for a certain DDT pathway in human cells.

DOI： 10.1371/journal.pone.0118775

UV-induced mutations in epidermal cells of mice defective in DNA polymerase eta and/or iota

Mechanisms of accurate translesion synthesis by human DNA polymerase h. 査読有り

Masutani, C., Kusumoto, R., Iwai, S., and Hanaoka, F.

EMBO J. 19 巻頁： 3100-3109 2000年

Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. 査読有り

Masutani, C., Araki, M., Yamada, A., Kusumoto, R., Nogimori, T., Maekawa, T., Iwai, S., and Hanaoka, F.

EMBO J. 18 巻頁： 3491-3501 1999年

The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase h. 査読有り

Masutani, C., Kusumoto, R., Yamada, A., Dohmae, N., Yokoi, M., Yuasa, M., Araki, M., Iwai, S., Takio, K., and Hanaoka, F.

Nature 399 巻頁： 700-704 1999年

Acetaldehyde induces NER repairable mutagenic DNA lesions. 査読有り

Sonohara Y, Takatsuka R, Masutani C, Iwai S, Kuraoka I

Carcinogenesis 2021年9月

Stepwise multipolyubiquitination of p53 by the E6AP-E6 ubiquitin ligase complex 査読有り

Masuda Yuji, Saeki Yasushi, Arai Naoko, Kawai Hidehiko, Kukimoto Iwao, Tanaka Keiji, Masutani Chikahide

JOURNAL OF BIOLOGICAL CHEMISTRY 294 巻 ( 41 ) 頁： 14860 - 14875 2019年10月

Spatiotemporal regulation of PCNA ubiquitination in damage tolerance pathways 査読有り

Masuda Yuji, Masutani Chikahide

CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY 54 巻 ( 5 ) 頁： 418 - 442 2019年9月

Preferential digestion of PCNA-ubiquitin and p53-ubiquitin linkages by USP7 to remove polyubiquitin chains from substrates. 査読有り

Masuda Y, Kanao R, Kawai H, Kukimoto I, Masutani C

The Journal of biological chemistry 2019年1月

Regulation of DNA damage tolerance in mammalian cells by post-translational modifications of PCNA 査読有り

Kanao Rie, Masutani Chikahide

MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS 803 巻頁： 82 - 88 2017年10月

Biochemical analysis of HLTF, a human homologue of SWI/SNF-related ubiquitin ligase RAD5

Masuda Yuji, Kanao Rie, Masutani Chikahide

GENES & GENETIC SYSTEMS 91 巻 ( 6 ) 頁： 366 - 366 2016年12月

Stimulation of human DNA polymerase eta by PCNA

Masuda Yuji, Kanao Rie, Masutani Chikahide

GENES & GENETIC SYSTEMS 90 巻 ( 6 ) 頁： 368 - 368 2015年12月

The BAH domain of BAF180 is required for PCNA ubiquitination. 査読有り

Niimi A, Hopkins SR, Downs JA, Masutani C

Mutation Research 779 巻頁： 16-23 2015年6月

UV-induced mutations in epidermal cells of mice defective in DNA polymerase η and/or ι. 査読有り

Kanao R., Yokoi M., Ohkumo T., Sakurai Y., Dotsu K., Kura S., Nakatsu Y., Tsuzuki T., Masutani C., Hanaoka F.

DNA Repair (Amst) 29 巻頁： 139-146 2015年5月

Kanao Rie, Yokoi Masayuki, Ohkumo Tsuyoshi, Sakurai Yasutaka, Dotsu Kantaro, Kura Shinobu, Nakatsu Yoshimichi, Tsuzuki Teruhisa, Masutani Chikahide, Hanaoka Fumio

DNA REPAIR 29 巻頁： 139 - 146 2015年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：DNA Repair

Xeroderma pigmentosum variant (XP-V) is a human rare inherited recessive disease, predisposed to sunlight-induced skin cancer, which is caused by deficiency in DNA polymerase η (Polη). Polη catalyzes accurate translesion synthesis (TLS) past pyrimidine dimers, the most prominent UV-induced lesions. DNA polymerase ι (Polι) is a paralog of Polη that has been suggested to participate in TLS past UV-induced lesions, but its function in vivo remains uncertain. We have previously reported that Polη-deficient and Polη/Polι double-deficient mice showed increased susceptibility to UV-induced carcinogenesis. Here, we investigated UV-induced mutation frequencies and spectra in the epidermal cells of Polη- and/or Polι-deficient mice. While Polη-deficient mice showed significantly higher UV-induced mutation frequencies than wild-type mice, Polι deficiency did not influence the frequencies in the presence of Polη. Interestingly, the frequencies in Polη/Polι double-deficient mice were statistically lower than those in Polη-deficient mice, although they were still higher than those of wild-type mice. Sequence analysis revealed that most of the UV-induced mutations in Polη-deficient and Polη/Polι double-deficient mice were base substitutions at dipyrimidine sites. An increase in UV-induced mutations at both G:C and A:T pairs associated with Polη deficiency suggests that Polη contributes to accurate TLS past both thymine- and cytosine-containing dimers in vivo. A significant decrease in G:C to A:T transition in Polη/Polι double-deficient mice when compared with Polη-deficient mice suggests that Polι is involved in error-prone TLS past cytosine-containing dimers when Polη is inactivated.

DOI： 10.1016/j.dnarep.2015.02.006

P-002 PCNAとヒトDNAポリメラーゼηの相互作用(ポスターセッション,ゲノム変異の生成と抑制 : 分子メカニズムの理解からレギュラトリーサイエンスへ)

Relevance of simultaneous mono-ubiquitnations of multiple units of PCNA homo-trimers in DNA damage tolerance. 査読有り

Kanao R, Masuda Y, Deguchi S, Yumoto-Sugimoto M, Hanaoka F, Masutani C

PLoS One 10 巻 ( 2 ) 頁： e0118775 2015年2月

増田雄司, 金尾梨絵, 益谷央豪

日本環境変異原学会大会プログラム・要旨集 ( 44 ) 2015年

Analysis of PCNA interacting motifs of DNA polymerase

Masuda Yuji, Kanao Rie, Ohmori Haruo, Hanaoka Fumio, Masutani Chikahide

GENES & GENETIC SYSTEMS 89 巻 ( 6 ) 頁： 309 - 309 2014年12月

Sphingosine, a Modulator of Human Translesion DNA Polymerase Activity

Kamath-Loeb Ashwini S., Balakrishna Sharath, Whittington Dale, Shen Jiang-Cheng, Emond Mary J., Okabe Takayoshi, Masutani Chikahide, Hanaoka Fumio, Nishimura Susumu, Loeb Lawrence A.

JOURNAL OF BIOLOGICAL CHEMISTRY 289 巻 ( 31 ) 頁： 21663 - 21672 2014年8月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

Translesion (TLS) DNA polymerases are specialized, error-prone enzymes that synthesize DNA across bulky, replication-stalling DNA adducts. In so doing, they facilitate the progression of DNA synthesis and promote cell proliferation. To potentiate the effect of cancer chemotherapeutic regimens, we sought to identify inhibitors of TLS DNA polymerases. We screened five libraries of ∼3000 small molecules, including one comprising ∼600 nucleoside analogs, for their effect on primer extension activity of DNA polymerase η (Polη). We serendipitously identified sphingosine, a lipid-signaling molecule that robustly stimulates the activity of Pol η by ∼100-fold at low micromolar concentrations but inhibits it at higher concentrations. This effect is specific to the Y-family DNA polymerases, Pols η, κ, and ι. The addition of a single phosphate group on sphingosine completely abrogates this effect. Likewise, the inclusion of other sphingolipids, including ceramide and sphingomyelin to extension reactions does not elicit this response. Sphingosine increases the rate of correct and incorrect nucleotide incorporation while having no effect on polymerase processivity. Endogenous Pol η activity is modulated similarly as the recombinant enzyme. Importantly, sphingosine-treated cells exhibit increased lesion bypass activity, and sphingosine tethered to membrane lipids mimics the effects of free sphingosine. Our studies have uncovered sphingosine as a modulator of TLS DNA polymerase activity; this property of sphingosine may be associated with its known role as a signaling molecule in regulating cell proliferation in response to cellular stress. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M114.570242

Sphingosine: A Modulator of Human Translesion DNA Polymerase Activity. 査読有り

Kamath-Loeb AS, Balakrishna S, Whittington D, Shen JC, Emond MJ, Okabe T, Masutani C, Hanaoka F, Nishimura S, Loeb LA.

Journal of Biological Chemistry 2014年7月

Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication 査読有り国際誌

Shibutani Toshihiro, Ito Shinsuke, Toda Mariko, Kanao Rie, Collins Leonard B., Shibata Marika, Urabe Miho, Koseki Haruhiko, Masuda Yuji, Swenberg James A., Masutani Chikahide, Hanaoka Fumio, Iwai Shigenori, Kuraoka Isao

SCIENTIFIC REPORTS 4 巻頁： 5220 - 5220 2014年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

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. © 2014 Macmillan Publishers Limited. All rights reserved.

DOI： 10.1038/srep05220

A cyclobutane thymine-N-4-methylcytosine dimer is resistant to hydrolysis but strongly blocks DNA synthesis 査読有り国際誌

Yamamoto Junpei, Oyama Tomoko, Kunishi Tomohiro, Masutani Chikahide, Hanaoka Fumio, Iwai Shigenori

NUCLEIC ACIDS RESEARCH 42 巻 ( 3 ) 頁： 2075 - 2084 2014年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nucleic Acids Research

Exposure of DNA to ultraviolet light produces harmful crosslinks between adjacent pyrimidine bases, to form cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone photoproducts. The CPD is frequently formed, and its repair mechanisms have been exclusively studied by using a CPD formed at a TT site. On the other hand, biochemical analyses using CPDs formed within cytosine-containing sequence contexts are practically difficult, because saturated cytosine easily undergoes hydrolytic deamination. Here, we found that N-Alkylation of the exocyclic amino group of 2′-deoxycytidine prevents hydrolysis in CPD formation, and an N-methylated cytosine-containing CPD was stable enough to be derivatized into its phosphoramidite building block and incorporated into oligonucleotides. Kinetic studies of the CPD-containing oligonucleotide indicated that its lifetime under physiological conditions is relatively long (∼7 days). In biochemical analyses using human DNA polymerase η, incorporation of TMP opposite the N-methylcytosine moiety of the CPD was clearly detected, in addition to dGMP incorporation, and the incorrect TMP incorporation blocked DNA synthesis. The thermodynamic parameters confirmed the formation of this unusual base pair. © 2013 The Author(s) 2013. Published by Oxford University Press.

DOI： 10.1093/nar/gkt1039

En bloc transfer of polyubiquitin chains to PCNA in vitro is mediated by two different human E2-E3 pairs

Interactions between PCNA and DNA polymerases of Y-family

Masuda Yuji, Kanao Rie, Masutani Chikahide

GENES & GENETIC SYSTEMS 88 巻 ( 6 ) 頁： 360 - 360 2013年12月

Novel mechanisms of PCNA ubiquitination

Masuda Yuji, Masutani Chikahide

GENES & GENETIC SYSTEMS 87 巻 ( 6 ) 頁： 387 - 387 2012年12月

En bloc transfer of poly-ubiquitin chains to PCNA in vitro is mediated by two human E2-E3 pairs. 査読有り

*Masuda, Y., Suzuki, M., Kawai, H., Hishiki, A., Hashimoto, H., Masutani, C., Hishida, T., Suzuki, F., *Kamiya. K.

Nucl. Acids Res. 40 巻 ( 20 ) 頁： 10394-10407 2012年11月

Masuda Yuji, Suzuki Miki, Kawai Hidehiko, Hishiki Asami, Hashimoto Hiroshi, Masutani Chikahide, Hishida Takashi, Suzuki Fumio, Kamiya Kenji

NUCLEIC ACIDS RESEARCH 40 巻 ( 20 ) 頁： 10394 - 10407 2012年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Nucleic Acids Research

Post-replication DNA repair in eukaryotes is regulated by ubiquitination of proliferating cell nuclear antigen (PCNA). Monoubiquitination catalyzed by RAD6-RAD18 (an E2-E3 complex) stimulates translesion DNA synthesis, whereas polyubiquitination, promoted by additional factors such as MMS2-UBC13 (a UEV-E2 complex) and HLTF (an E3 ligase), leads to template switching in humans. Here, using an in vitro ubiquitination reaction system reconstituted with purified human proteins, we demonstrated that PCNA is polyubiquitinated predominantly via en bloc transfer of a pre-formed ubiquitin (Ub) chain rather than by extension of the Ub chain on monoubiquitinated PCNA. Our results support a model in which HLTF forms a thiol-linked Ub chain on UBC13 (UBC13∼Ubn) and then transfers the chain to RAD6∼Ub, forming RAD6∼Ubn+1. The resultant Ub chain is subsequently transferred to PCNA by RAD18. Thus, template switching may be promoted under certain circumstances in which both RAD18 and HLTF are coordinately recruited to sites of stalled replication. © 2012 The Author(s).

DOI： 10.1093/nar/gks763

Human DNA Polymerase η and Its Regulatory Mechanisms

Masutani Chikahide

Genes and environment : the official journal of the Japanese Environmental Mutagen Society 34 巻 ( 2 ) 頁： 63 - 69 2012年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：日本環境変異原学会

Defects in DNA polymerase (Pol) η result in a cancer-prone and UV-sensitive inherited syndrome, a variant form of xeroderma pigmentosum, suggesting that Polη plays a vital role in preventing UV-induced skin cancers. In fact, Polη can catalyze translesion synthesis (TLS) past prominent UV-induced lesions efficiently and accurately. However, Polη is intrinsically an error-prone DNA polymerase, like other TLS polymerases. Biochemical, structural and physiological studies revealed that Polη and other TLS polymerases participate in multiple mutagenic mechanisms, including somatic hypermutation of immunoglobulin genes. Protein-protein interactions between Polη and PCNA, TLS polymerases, RAD18 and DNA repair proteins, as well as their posttranslational modifications, have been shown to be important for regulating Polη.<br>

DOI： 10.3123/jemsge.34.63

NBS1 Recruits RAD18 via a RAD6-like Domain and Regulates Pol eta-Dependent Translesion DNA Synthesis

Yanagihara Hiromi, Kobayashi Junya, Tateishi Satoshi, Kato Akihiro, Matsuura Shinya, Tauchi Hiroshi, Yamada Kouichi, Takezawa Jun, Sugasawa Kaoru, Masutani Chikahide, Hanaoka Fumio, Weemaes Corry M., Mori Toshio, Zou Lee, Komatsu Kenshi

MOLECULAR CELL 43 巻 ( 5 ) 頁： 788 - 797 2011年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Cell

Translesion DNA synthesis, a process orchestrated by monoubiquitinated PCNA, is critical for DNA damage tolerance. While the ubiquitin-conjugating enzyme RAD6 and ubiquitin ligase RAD18 are known to monoubiquitinate PCNA, how they are regulated by DNA damage is not fully understood. We show that NBS1 (mutated in Nijmegen breakage syndrome) binds to RAD18 after UV irradiation and mediates the recruitment of RAD18 to sites of DNA damage. Disruption of NBS1 abolished RAD18-dependent PCNA ubiquitination and Polη focus formation, leading to elevated UV sensitivity and mutation. Unexpectedly, the RAD18-interacting domain of NBS1, which was mapped to its C terminus, shares structural and functional similarity with the RAD18-interacting domain of RAD6. These domains of NBS1 and RAD6 allow the two proteins to interact with RAD18 homodimers simultaneously and are crucial for Polη-dependent UV tolerance. Thus, in addition to chromosomal break repair, NBS1 plays a key role in translesion DNA synthesis. © 2011 Elsevier Inc.

DOI： 10.1016/j.molcel.2011.07.026

The Molecular Chaperone Hsp90 Regulates Accumulation of DNA Polymerase eta at Replication Stalling Sites in UV-Irradiated Cells

NBS1 recruits RAD18 via a RAD6-like domain and regulates Polh-dependent translesion DNA synthesis. 査読有り

Yanagihara, H., Kobayashi, J., Tateishi, S., Kato, A., Matsuura, S., Tauchi, H., Yamada, K., Takwzawa, J., Sugasawa, K., Masutani, C., Hanaoka, F., Weemaes, C.M., Mori, T., Zou, L., Komatsu. K.

Mol. Cell 43 巻 ( 5 ) 頁： 788-797 2011年9月

Molecular chaperone Hsp90 regulates REV1-mediated mutagenesis 査読有り

Pozo, F.M., Oda, T., sekimoto, T., Murakumo, Y., Masutani, C., Hanaoka, F., Yamashita, T.

Mol. Cell. Biol. 31 巻 ( 16 ) 頁： 3396-3409 2011年8月

Photosensitized [2+2] cycloaddition of N-acetylated cytosine affords stereoselective formation of cyclobutane pyrimidine dimer. 査読有り

Yamamoto, J., nishiguchi, K., Manabe, K., Masutani, C., Hanaoka, F., Iwai, S.

Nucl. Acids Res. 39 巻頁： 1165-1175 2011年2月

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.

Hirota K, Sonoda E, Kawamoto T, Motegi A, Masutani C, Hanaoka F, Szüts D, Iwai S, Sale JE, Lehmann A, Takeda S

PLoS genetics 6 巻 ( 10 ) 2010年10月

Simultaneous disruption of two DNA polymerases, Polh and Polz, in Avian DT40 cells unmasks the role of Polh in cellular response to various DNA lesions. 査読有り

Hirota, K., Sonoda, E., Kawamoto, T., Motegi, A., Masutani, C., Hanaoka, F., Szuts, D., Iwai, S., Sale, J.E., Lehmann, A., Takeda, S.

PLoS Genet. 6 巻 ( 10 ) 2010年10月

Characterization of a Y-Family DNA Polymerase eta from the Eukaryotic Thermophile Alvinella pompejana.

Kashiwagi S, Kuraoka I, Fujiwara Y, Hitomi K, Cheng QJ, Fuss JO, Shin DS, Masutani C, Tainer JA, Hanaoka F, Iwai S

Journal of nucleic acids 2010 巻 2010年9月

Characterization of a Y-family DNA polymerase h from the eukaryotic thermophile Alvinella pompejana. 査読有り

Kashiwagi, S., kuraoka, I., fujiwara, Y., Hitomi, K., Cheng, Q.J., Fuss, J.O., Shin, D.S., Masutani, C., Tainer, J.A., Hanaoka, F., Iwai, S.

J. Nucl. Acids 2010 巻 2010年9月

Structure and mechanism of human DNA polymerase eta.

Biertümpfel C, Zhao Y, Kondo Y, Ramón-Maiques S, Gregory M, Lee JY, Masutani C, Lehmann AR, Hanaoka F, Yang W

Nature 465 巻 ( 7301 ) 頁： 1044 - 8 2010年6月

Structure and mechanism of human DNA polymerase h. 査読有り

Biertümpfel, C., Zhao, Y., Kondo, Y., Ramón-Maiques, S., Gregory, M., Lee, J.Y., Masutani, C., Lehmann, A. R., *Hanaoka, F., and *Yang, W.

Nature 465 巻頁： 1044-1048 2010年6月

Polymerization by DNA polymerase h is blocked by cis-diamminedichloroplatinum(II) 1,3-d(GpTpG) crosslink: Implications for cytotoxic effects in nucleotide excision repair-negative tumor cells. 査読有り

Chijiwa, S., Masutani, C., Hanaoka, F., Iwai, S., and *Kuraoka, I.

Carcinogenesis 31 巻頁： 388-393 2010年3月

Polymerization by DNA polymerase eta is blocked by cis-diamminedichloroplatinum(II) 1,3-d(GpTpG) cross-link: implications for cytotoxic effects in nucleotide excision repair-negative tumor cells.

Chijiwa S, Masutani C, Hanaoka F, Iwai S, Kuraoka I

Carcinogenesis 31 巻 ( 3 ) 頁： 388 - 93 2010年3月

Sekimoto Takayuki, Oda Tsukasa, Pozo Franklin Mayca, Murakumo Yoshiki, Masutani Chikahide, Hanaoka Fumio, Yamashita Takayuki

MOLECULAR CELL 37 巻 ( 1 ) 頁： 79 - 89 2010年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Molecular Cell

DNA polymerase η (Pol η) is a member of the mammalian Y family polymerases and performs error-free translesion synthesis across UV-damaged DNA. For this function, Pol η accumulates in nuclear foci at replication stalling sites via its interaction with monoubiquitinated PCNA. However, little is known about the posttranslational control mechanisms of Pol η, which regulate its accumulation in replication foci. Here, we report that the molecular chaperone Hsp90 promotes UV irradiation-induced nuclear focus formation of Pol η through control of its stability and binding to monoubiquitinated PCNA. Our data indicate that Hsp90 facilitates the folding of Pol η into an active form in which PCNA- and ubiquitin-binding regions are functional. Furthermore, Hsp90 inhibition potentiates UV-induced cytotoxicity and mutagenesis in a Pol η-dependent manner. Our studies identify Hsp90 as an essential regulator of Pol η-mediated translesion synthesis. © 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.molcel.2009.12.015