Elucidation of the ubiquitin pathway that removes adducts attached to DNA double-strand breaks
Project/Area Number |
19H04267
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 63020:Radiation influence-related
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Research Institution | Tokyo Metropolitan Institute of Medical Science (2021) Kyoto University (2019-2020) |
Principal Investigator |
SASANUMA Hiroyuki 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 副参事研究員 (00531691)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
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Keywords | がん / DNA修復 / 相同組換え / DNA二重鎖切断 / BRCA1 / トポイソメラーゼ2型 / UBC13 / DNA損傷 / トポイソメラーゼ / 放射線 / 付加体 / ユビキチン / DNA二重鎖切断修復 / ゲノム編集 / トポイソメラーゼ2 |
Outline of Research at the Start |
細胞内にできるDNA切断は、5’リン酸基、3’水酸基がついた「きれい」な傷ではない。DNA切断端周辺に塩基やリボース環損傷を含んだ「汚い」傷である。こうした「汚い」傷は、相同組換えや非相同末端結合のようなDNA修復の前に、「きれいな」傷に直される必要がある。「汚い」傷が「きれいな」傷に直されるメカニズムは分かっていない。本研究では、「汚い」傷を作る放射線と抗がん剤(エトポシド)と「きれいな」傷を作る制限酵素によってできるDNA切断を比較することにより、「汚い」傷が「きれいな」傷に直される経路を明らかにする。この経路に関与する因子の阻害は、放射線治療の増感作用をもたらす可能性がある。
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Outline of Final Research Achievements |
DNA double strand breaks (DSBs) are mainly repaired by Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). While the ends of DSBs induced by restriction enzyme harbor 5’-phosphate and 3’-hydroxy group, those induced by ionizing radiation (IR) do not. IR induces DSBs with a variety of chemical modifications at DSB end-proximal regions. Such DSBs with chemical/protein adducts interfere DSB repair process. The molecular mechanism by which the adducts at DSB sites are processed remains elusive. The aim of this research project is to clarify its molecular mechanism of adduct removal from DSB-ends. We identified the molecules involved in adduct removal. Ubiquitin E2 ligase UBC13-dependent ubiquitination at the DSB end-proximal region promotes the removal of adducts and its repair by NHEJ. We proposed a model that the ubiquitinated proteins are recognized by RAP80-BRCA1, which transfers its DNA damaging signal to MRE11 nuclease to adduct removal.
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Academic Significance and Societal Importance of the Research Achievements |
抗がん治療では、放射線照射によりDNA損傷を与え腫瘍細胞を殺傷する。放射線感受性を高める増感剤は、治療効果を高めるのみならず照射線量を減らすことにつながる。本研究では、放射線によって切断端に発生する塩基損傷や蛋白質付加体の除去機構を明らかにした。本研究で同定したUBC13ユビキチン化酵素依存的な付加体除去の分子機構をもとに、放射線増感剤開発が可能となる。放射線生物学において、「切断端に発生する塩基損傷や蛋白質付加体の除去」の分子機構は長らく不明であったが、本研究によってその分子メカニズムの一端が明らかとなった。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development2021
Author(s)
Moribe F, Nishikori M, Takashima T, Taniyama D, Onishi N, Arima H, Sasanuma H, Akagawa R, Elloumi F, Takeda S, Pommier Y, Morii E, Takaori-Kondo A, Murai J.
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Journal Title
PLoS One.
Volume: 16
Issue: 1
Pages: 0237554-0237554
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination.2020
Author(s)
Rahman MM, Mohiuddin M, Shamima Keka I, Yamada K, Tsuda M, Sasanuma H, Andreani J, Guerois R, Borde V, Charbonnier JB, Takeda S.
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Journal Title
J Biol Chem.
Volume: 295
Issue: 51
Pages: 17460-17475
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells2020
Author(s)
Toshiaki Nakano, Mahmoud I. Shoulkamy, Masataka Tsuda, Hiroyuki Sasanuma, Kouji Hirota, Minoru Takata, Shin-ichiro Masunaga, Shunichi Takeda, Hiroshi Ide, Tadayoshi Bessho, Keizo Tano
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Journal Title
PLOS ONE
Volume: 15
Issue: 6
Pages: 0234859-0234859
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells2020
Author(s)
Saha Liton Kumar、Wakasugi Mitsuo、Akter Salma、Prasad Rajendra、Wilson Samuel H.、Shimizu Naoto、Sasanuma Hiroyuki、Huang Shar-yin Naomi、Agama Keli、Pommier Yves、Matsunaga Tsukasa、Hirota Kouji、Iwai Shigenori、Nakazawa Yuka、Ogi Tomoo、Takeda Shunichi
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Journal Title
Proceedings of the National Academy of Sciences
Volume: 117
Issue: 25
Pages: 14412-14420
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.2020
Author(s)
Mahmud MRA, Ishii K, Lozano CB, Sainz ID, Toi M, Akamatsu S, Fukumoto M, Watanabe M, Takeda S, Ledesma FC, Sasanuma H.
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Journal Title
Genes to Cells
Volume: in press
Issue: 7
Pages: 450-465
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations2019
Author(s)
Gothe HJ, Bouwman BAM, Gusmao EG, Piccinno R, Petrosino G, Sayols S, Drechsel O, Minneker V, Josipovic N, Mizi A, Nielsen CF, Wagner EM, Takeda S, Sasanuma H, et al
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Journal Title
Molecular Cell
Volume: 75
Issue: 2
Pages: 267-283.e12
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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