Genome organization as a source of chromosomal instability in cancer.

2021 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

Genome organization

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