Genome organization as a source of chromosomal instability in cancer.

• Project/Area Number: 19H03208
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: Kyoto University
• Principal Investigator: Canela Andres 京都大学, 白眉センター, 特定准教授 (90837585)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2020: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2019: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: TOPOISOMERASEII / DNA 二重鎖切断 / 染色体転座発かん / ゲノム安定性 / 発かん / 染色体転座 / TOPOISOMERASE2

Outline of Research at the Start

Folding of the DNA is a source of genome instability that leads to cancer. Topoisomerase 2 (TOP2) releases torsions during DNA organization, but generates transient DNA breaks that can drive genome instability and cancer. I will study the role of TOP2 in genome organization and genome instability.

Outline of Final Research Achievements

The DNA is packed and folded in loops to fit inside the nucleus. This compression in the DNA leads to torsions that are dissipated by the enzyme topoisomerase type II (TOP2). TOP2 acts in the same locations where the DNA folds to form loops. I found that the role of TOP2 in these locations is to facilitate compaction of the DNA during loop formation. During its normal enzymatic activity, TOP2 temporary cuts and reseal the DNA to relax torsions, but sometimes it fails resealing the breaks and becomes trapped in the DNA. These breaks have to be repaired and can lead to DNA damage, chromosomal aberrations and cancer. I quantified how TOP2 breaks leads to chromosomal translocations and found that although the initial breaks caused by TOP2 activity depend on the folding of the DNA, transcription is responsible of processing these breaks increasing genome instability and leading to oncogenic chromosomal translocations.

Academic Significance and Societal Importance of the Research Achievements

Clarifying the role of TOP2 in genome organization is necessary to understand how genome structure relates to nuclear function. In addition, finding that transcription drives conversion of TOP2 breaks into chromosomal translocations can be used to avoid oncogenic chromosomal aberrations and leukemia

Research Products

• [Int'l Joint Research] National Institutes of Health(米国)
• [Journal Article] END-seq: An Unbiased, High-Resolution, and Genome-Wide Approach to Map DNA Double-Strand Breaks and Resection in Human Cells (2021)
  • Author(s): Wong N, John S, Nussenzweig A, Canela A.
  • Journal Title: Methods in Molecular Biology Volume: 2153 Pages: 9-31
  • DOI: 10.1007/978-1-0716-0644-5_2
  • ISBN: 9781071606438, 9781071606445
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes (2021)
  • Author(s): Huang SN, Michaels SA, Mitchell BB, Majdalani N, Vanden Broeck A, Canela A, Tse-Dinh YC, Lamour V, Pommier Y.
  • Journal Title: Science Advances Volume: 7 Issue: 10
  • DOI: 10.1126/sciadv.abe0384
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuronal enhancers are hotspots for DNA single-strand break repair. (2021)
  • Author(s): Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colon-Mercado JM, Zong D, De Pace R, Shih HY, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW, Ward ME, Nussenzweig A.
  • Journal Title: Nature Volume: online Issue: 7859 Pages: 440-444
  • DOI: 10.1038/s41586-021-03468-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination. (2020)
  • Author(s): Callen E, Zong D, Wu W, Wong N, Stanlie A, Ishikawa M, Pavani R, Dumitrache LC, Byrum AK, Mendez-Dorantes C, Martinez P, Canela A, Maman Y, Day A, Kruhlak MJ, Blasco MA, Stark JM, Mosammaparast N, McKinnon PJ, Nussenzweig A
  • Journal Title: Molecular Cell Volume: 77 Issue: 1 Pages: 26-38
  • DOI: 10.1016/j.molcel.2019.09.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Topoisomerase II-Induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity. (2019)
  • Author(s): Canela A, Maman Y, Huang SN, Wutz G, Tang W, Zagnoli-Vieira G, Callen E, Wong N, Day A, Peters JM, Caldecott KW, Pommier Y, Nussenzweig A
  • Journal Title: Molecular Cell Volume: 75 Issue: 2 Pages: 252-266
  • DOI: 10.1016/j.molcel.2019.04.030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intra-V? Cluster Recombination Shapes the Ig Kappa Locus Repertoire (2019)
  • Author(s): Shinoda K, Maman Y, Canela A, Schatz DG, Livak F, Nussenzweig A
  • Journal Title: Cell Reports Volume: 29 Issue: 13 Pages: 4471-4481
  • DOI: 10.1016/j.celrep.2019.11.088
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] How to find breaks in the DNA and what they can tell us about genome organization (2020)
  • Author(s): Andres Canela
  • Organizer: Central Dogma Seminar. Graduate School of Biostudies. Kyoto University
  • Invited
• [Presentation] Topoisomerase II-induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. (2019)
  • Author(s): Andres Canela
  • Organizer: EMBO Workshop: Organization of bacterial and eukaryotic genomes by SMC complexes. Vienna, Austria
  • Int'l Joint Research / Invited
• [Presentation] Topoisomerase II-induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. (2019)
  • Author(s): Andres Canela
  • Organizer: EMBO Workshop: DNA topology and topoisomerases in genome dynamics. Les Diablerets, Switzerland
  • Int'l Joint Research
• [Presentation] Genome folding as a source of DNA damage and tumorigenesis (2019)
  • Author(s): Andres Canela
  • Organizer: 21st Symposium of Graduate School of Biostudies. Kyoto University
  • Invited