Cancer Genome Dynamics Project｜Laboratories

Update : 2023-10-19

Overview

Failure in the process of DNA replication leads to genetic changes in daughter cells and potentially causes cancer predisposition in our body. Mutations were frequently found in polymerase genes in cancer cells, implicating that variation in function of DNA polymerase(s) contributes to the development of cancer. We characterise properties of DNA replication in cancer cells and then try to develop new insights about potential causes, treatments and biomarkers of cancer.

Research

During each cell division, genomic information must be efficiently replicated and subsequently segregated at mitosis. However, the process of replication is not without incident - it is well established that the replication machinery encounters various obstacles and is designed to have a degree of flexibility, allowing cells to tolerate the problem within limited time during S phase. There are more than 10 DNA polymerases encoded in eukaryotic cells and two polymerases (Polδ and Polε) replicate the bulk of parental DNA. On the other hand, some of other polymerases are less processive but tolerant replication blockage. We know little about how activities of DNA polymerases are coordinated during genome replication. We principally tackle this issue by combining molecular genetics with genome science.

Selected publications

Koyanagi, Y. Kakimoto, T. Minamisawa, F. Yoshifuji, T. Natsume, A. Higashitani, T. Ogi, A. M. Carr, M. T. Kanemaki, Y. Daigaku: Global landscape of replicative DNA polymerase usage in the human genome, Nat Commun, 13, 7221, 2022
Y. Nakazawa, Y. Hara, Y. Oka, O.Komine, D. Heuvel, C.Guo, Y. Daigaku, M. Isono, Y. He, M. Shimada, K. Kato, N. Jia, S. Hashimoto, Y. Kotani, Y. Miyoshi, M. Tanaka, A. Sobue, No. Mitsutake, T. Suganami, A. Masuda, K. Ohno, S. Nakada, T. Mashimo, K. Yamanaka, M.S. Luijsterburg, Tomoo Ogi: Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. Cell, 1228-1244, 180, 2020
Z. Shao, S. Niwa, A. Higashitani, Y. Daigaku: Vital roles of PCNA K165 modification during C. elegans gametogenesis and embryogenesis. DNA Repair, 82, 102688, 2019
N. García-Rodríguez, M. Morawska, R. P. Wong, Y. Daigaku, H. D. Ulrich: Spatial separation between replisome- and template- induced replication stress signalling, EMBO J. 3, e98369, 2018
Y. Daigaku, T.J. Etheridge, Y. Nakazawa, M. Nakayama, A.T. Watson, I. Miyabe, T. Ogi, M.A. Osborne, A.M. Carr: PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast. PLoS Genet 13(5): e1006789, 2017
Y. Daigaku, A. Keszthelyi, C. A. Müller I. Miyabe, T. Brooks, R. Retkute, M. Hubank, C. A. Nieduszyski, A. M. Carr: A global profile of replicative polymerase usage, Nat. Struct. Mol. Biol. 22, 192-8, 2015
A. Keszthelyi, Y. Daigaku, K. Ptasińska, I. Miyabe, A. M. Carr: Mapping ribonucleotides in genomic DNA and exploring replication dynamics by polymerase usage sequencing (Pu-seq), Nat. Protocol. 10, 1786-801, 2015
Miyabe, K. Mizuno, A. Keszthelyi, Y. Daigaku, M. Skouteri, S. Mohebi, T. A. Kunkel, J. M. Murray, A. M. Carr: Polymerase δ replicates both strands after homologous recombination-dependent fork restart, Nat. Struct. Mol. Biol. 22, 932-938, 2015
Y. Daigaku, A. A. Davies and H. D. Ulrich: Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature. 465, 951-955, 2010
Davies, D. Huttner, Y. Daigaku, S. Chen and H. D. Ulrich: Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein A. Mol Cell. 29, 625-636, 2008

Contact

Yasukazu Daigaku
Japanese Foundation for Cancer Research (JFCR)
3-8-31 Ariake Koto-ku Tokyo, 135-8550
Tel. +81-3-3570-0509
E-mail: yasukazu.daigaku@jfcr.or.jp