Medical Sciences Group／Inter-Institute Cooperative LaboratoriesSasanuma Laboratory
(Biomedical Sciences Group, TMiMS)
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Visiting Professor SASANUMA Hiroyuki
Elucidating new principles of genome inheritance, maintenance and functional expression
The human genome, consisting of 3 billion base pairs, is frequently subject to damage from both external and internal factors. While most of the damage is correctly repaired, a few are not, resulting in base substitutions. Many of these substituted bases do not affect cellular function, but when base substitutions alter protein function, they could impact cellular phenotypes, such as growth rate and sensitivity to anti-cancer drugs. In some cases, cells emerge that can no longer halt their proliferation. These "cells that cannot stop proliferating" are, in essence, cancer cells. Our laboratory aims to understand the mechanisms underlying chromosome instability, one of the common characteristics of cancer. Chromosome instability refers to the inability to accurately transmit the quality and quantity of genomic information to daughter cells. For instance, the incorporation of incorrect bases by DNA polymerase during DNA replication and repair can lead to a decline in both the quality and the quantity of genomic information. Abnormalities in enzymes responsible for chromosome segregation can relatively result in a change in the quantity of genomic information. Our research group focuses on unraveling the mechanisms of chromosome instability caused by defects in DNA replication and DNA repair, as well as the resulting changes in genome dynamics. Our research team is focused on: ・Elucidating changes in three-dimensional genome structure resulting from chromosomal instability ・Investigating the impact of the relationship between nuclear genome organization and topology on genome function We are committed to enhancing our collaboration with Tokyo Metropolitan Hospitals, advancing our analyses of clinical specimens to gain deeper insights into molecular mechanism of disease onset. Our team utilizes cutting-edge technologies, including: ・Genome editing techniques ・High-resolution microscopy ・Single-cell transcriptomics ・Spatial transcriptomics and other cutting-edge next-generation sequencing technologies
- Research
keywords - DNA Replication DNA Damage and Repair Chromosome Dynamics Cancer Genome Genomic Instability Disorders DNA Topology
Investigating Disease Onset Mechanisms Caused by Impaired DNA Damage Repair
We are interested in understanding how diseases, particularly cancer, arise from deficiencies in DNA damage repair. To address this, we have generated mice that are deficient in DNA damage repair. Specifically, we are focusing on the BRCA genes, which play a crucial role in DNA repair, and elucidating the mechanisms by which mutations in these genes lead to disease onset.
Elucidation of Organ- and Tissue-Specific DNA Replication and Repair Mechanisms
DNA repair and replication research has a long-standing history, with numerous pathways and factors previously identified. Our current focus is on the DNA synthesis and repair systems in specific organs and tissues, with the goal of re-examining the basic mechanisms of DNA repair and replication. To achieve this, we employ advanced techniques such as long-range DNA sequencing using Nanopore technology and spatial transcriptomics.
References/papers
- References
- 1. "Najnin RA, Al Mahmud MR, Rahman MM, Takeda S, Sasanuma H, Tanaka H, Murakawa Y, Shimizu N, Akter S, Takagi M, Sunada T, Akamatsu S, He G, Itou J, Toi M, Miyaji M, Tsutsui KM, Keeney S, Yamada S.",ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen,Cell Rep. 2023 Jan 31;42(1):111909. doi: 10.1016/j.celrep.2022.111909. Epub 2022 Dec 30.,2023
- 2. "Akter S, Shimba A, Ikuta K, Mahmud MRA, Yamada S, Sasanuma H, Tsuda M, Sone M, Ago Y, Murai K, Tanaka H, Takeda S.",Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks,Genes Cells. 2023 Jan;28(1):53-67. doi: 10.1111/gtc.12993. Epub 2022 Dec 7.,2023
- 3. "Xu X, Xu Y, Guo R, Xu R, Fu C, Xing M, Sasanuma H, Li Q, Takata M, Takeda S, Guo R, Xu D.",Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress,Nat Struct Mol Biol. 2021 Jun;28(6):487-500. doi: 10.1038/s41594-021-00602-9. Epub 2021 Jun 10.,2021
- 4. "Demin AA, Hirota K, Tsuda M, Adamowicz M, Hailstone R, Brazina J, Gittens W, Kalasova I, Shao Z, Zha S, Sasanuma H, Hanzlikova H, Takeda S, Caldecott KW.",XRCC1 prevents toxic PARP1 trapping during DNA base excision repair,Mol Cell. 2021 Jul 15;81(14):3018-3030.e5. doi: 10.1016/j.molcel.2021.05.009. Epub 2021 Jun 7.,2021
- Key papers
- 1. "Sasanuma H, Tsuda M, Morimoto S, Saha LK, Rahman MM, Kiyooka Y, Fujiike H, Cherniack AD, Itou J, Callen Moreu E, Toi M, Nakada S, Tanaka H, Tsutsui K, Yamada S, Nussenzweig A, Takeda S.",BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes,Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10642-E10651. doi: 10.1073/pnas.1803177115. Epub 2018 Oct 23.,2018
- 2. "Hoa NN, Shimizu T, Zhou ZW, Wang ZQ, Deshpande RA, Paull TT, Akter S, Tsuda M, Furuta R, Tsutsui K, Takeda S, Sasanuma H.",Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes,Mol Cell. 2016 Dec 1;64(5):1010. doi: 10.1016/j.molcel.2016.11.028.,2016
- 3. "Zong D, Adam S, Wang Y, Sasanuma H, Callén E, Murga M, Day A, Kruhlak MJ, Wong N, Munro M, Ray Chaudhuri A, Karim B, Xia B, Takeda S, Johnson N, Durocher D, Nussenzweig A.",BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation,Mol Cell. 2019 Mar 21;73(6):1267-1281.e7. doi: 10.1016/j.molcel.2018.12.010. Epub 2019 Jan 28.,2019
Recent research results/papers
- "Yamazaki K, Iguchi T, Kanoh Y, Takayasu K, Ngo TTT, Onuki A, Kawaji H, Oshima S, Kanda T, Masai H, Sasanuma H.",Homologous recombination contributes to the repair of acetaldehyde-induced DNA damage,Cell Cycle. 2024 Feb;23(4):369-384. doi: 10.1080/15384101.2024.2335028. Epub 2024 Apr 3.,2024
