Faculty Profiles - NAKAZAWA Yuka

Comparing the severity of epidermolysis bullosa simplex harboring <i>KRT5</i> variants with the AlphaMissense score Open Access

Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair Reviewed International coauthorship

Yuka Nakazawa, Yuichiro Hara, Yasuyoshi Oka, Okiru Komine, Diana van den Heuvel, Chaowan Guo, Yasukazu Daigaku, Mayu Isono, Yuxi He, Mayuko Shimada, Kana Kato, Nan Jia, Satoru Hashimoto, Yuko Kotani, Yuka Miyoshi, Miyako Tanaka, Akira Sobue, Norisato Mitsutake, Takayoshi Suganami, Akio Masuda, Kinji Ohno, Shinichiro Nakada, Tomoji Mashimo, Koji Yamanaka, Martijn S. Luijsterburg, Tomoo Ogi

Cell Vol. 180 ( 6 ) page： 1228 - + 2020.3

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Reviewed International coauthorship

Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, Takahashi Y, Ohyama K, Ito K, Mishima H, Nomura M, Kinoshita A, Ono S, Takenaka K, Masuyama R, Kudo T, Slor H, Utani A, Tateishi S, Yamashita S, Stefanini M, Lehmann AR, Yoshiura KI, Ogi T§.

Nature Genetics Vol. 44 page： 586-592 2012.5

XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency. Reviewed International coauthorship

Guo C*, Nakazawa Y*, Woodbine L*, Bjorkman A, Shimada M, Fawcett H, Jia N, Ohyama K, Li TS, Nagayama Y, Mitsutake N, Pan-Hammarstrom Q, Gennery AR, Lehmann AR, Jeggo PA, Ogi T§.

Journal of Allergy and Clinical Immunology Vol. 136 page： 1007-1017 2015.10

A rapid comprehensive assay system for DNA repair activity and cytotoxic effects of DNA damaging reagents by measuring unscheduled DNA synthesis and recovery of RNA synthesis after DNA damage. Reviewed International coauthorship

Jia N*, Nakazawa Y*, Guo C, Shimada M, Sethi M, Takahashi Y, Ueda H, Nagayama Y, Ogi T§.

Nature Protocols Vol. 10 page： 12-24 2015.1

Malfunction of Nuclease ERCC1-XPF Results in Diverse Clinical Manifestations and Causes Cockayne Syndrome, Xeroderma Pigmentosum, and Fanconi Anemia. Reviewed International coauthorship

Kashiyama K*, Nakazawa Y*, Pilz D*, Guo C*, Shimada M, Sasaki K, Fawcett H, Wing J, Lewin S, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Yamashita S, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Takahashi Y, Nagayama Y, Mitsutake N, Lehmann AR§, Ogi T§.

American Journal of Human Genetics Vol. 92 page： 807-819 2013.5

Transcription-coupled repair -mechanisms of action, regulation, and associated human disorders. Invited Reviewed Open Access

Nakazawa Y, Oka Y, Matsunaga T, Ogi T

FEBS Letters Vol. 599 ( 2 ) page： 166 - 167 2025.1

Estimating the proportions of allele frequencies for SERPINA12 pathogenic variants in Japanese patients with Nagashima-type palmoplantar keratosis/keratoderma.

Ebata A, Takeichi T, Nishida K, Chretien B, Miyazaki A, Yoshikawa T, Suzuki Y, Tanahashi K, Fukaura R, Seishima M, Suga Y, Muro Y, Nakazawa Y, Ogi T, Akiyama M

The British journal of dermatology 2025.3

Omi, M; Takeichi, T; Yoshikawa, T; Inoue, Y; Fukaura, R; Hattori, I; Nakazawa, Y; Noda, T; Muro, Y; Akiyama, M

JOURNAL OF DERMATOLOGY Vol. 52 ( 3 ) page： e235 - e237 2025.3

Clearance of DNA damage-arrested RNAPII is selectively impaired in Cockayne syndrome cells

Paula J. van der Meer, George Yakoub, Yuka Nakazawa, Tomoo Ogi, Martijn Luijsterburg

2024.5

Inducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells. Reviewed International journal

Akiko Tomita, Hiroyuki Sasanuma, Tomoo Owa, Yuka Nakazawa, Mayuko Shimada, Takahiro Fukuoka, Tomoo Ogi, Shinichiro Nakada

Nature communications Vol. 14 ( 1 ) page： 5607 - 5607 2023.9

Language：English Publishing type：Research paper (scientific journal)

CRISPR/Cas9-mediated gene editing has great potential utility for treating genetic diseases. However, its therapeutic applications are limited by unintended genomic alterations arising from DNA double-strand breaks and random integration of exogenous DNA. In this study, we propose NICER, a method for correcting heterozygous mutations that employs multiple nicks (MNs) induced by Cas9 nickase and a homologous chromosome as an endogenous repair template. Although a single nick near the mutation site rarely leads to successful gene correction, additional nicks on homologous chromosomes strongly enhance gene correction efficiency via interhomolog homologous recombination (IH-HR). This process partially depends on BRCA1 and BRCA2, suggesting the existence of several distinct pathways for MN-induced IH-HR. According to a genomic analysis, NICER rarely induces unintended genomic alterations. Furthermore, NICER restores the expression of disease-causing genes in cells derived from genetic diseases with compound heterozygous mutations. Overall, NICER provides a precise strategy for gene correction.

DOI： 10.1038/s41467-023-41048-5

A case of Cockayne syndrome with unusually mild clinical manifestations. Reviewed

Tsujimoto M, Nakano E, Nakazawa Y, Kanda F, Ueda T, Ogi T, Nishigori C

Journal of Dermatology. Vol. 50 ( 4 ) page： 541 - 545 2023.4

Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test. Reviewed International journal

Chikako Senju, Yuka Nakazawa, Mayuko Shimada, Dai Iwata, Michiko Matsuse, Katsumi Tanaka, Yasushi Miyazaki, Shinichi Moriwaki, Norisato Mitsutake, Tomoo Ogi

Frontiers in pediatrics Vol. 10 page： 1048002 - 1048002 2022.11

Language：English Publishing type：Research paper (scientific journal)

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

DOI： 10.3389/fped.2022.1048002

Dealing with transcription-blocking DNA damage: Repair mechanisms, RNA polymerase II processing and human disorders Reviewed International coauthorship

Jia, N; Guo, CW*; Nakazawa, Y*; van den Heuvel, D*; Luijsterburg, MS; Ogi, T

DNA REPAIR Vol. 106 page： 103192 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：DNA Repair

Transcription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and fully block transcription when unresolved. The toxic impact of DNA damage on transcription progression is commonly referred to as transcription stress. In response to RNA Pol II stalling, cells activate and employ transcription-coupled repair (TCR) machineries to repair cytotoxic TBLs and resume transcription. Increasing evidence indicates that the modification and processing of stalled RNA Pol II is an integral component of the cellular response to and the repair of TBLs. If TCR pathways fail, the prolonged stalling of RNA Pol II will impede global replication and transcription as well as block the access of other DNA repair pathways that may act upon the TBL. Consequently, such prolonged stalling will trigger profound genome instability and devastating clinical features. In this review, we will discuss the mechanisms by which various types of TBLs are repaired by distinct TCR pathways and how RNA Pol II processing is regulated during these processes. We will also discuss the clinical consequences of transcription stress and genotype-phenotype correlations of related TCR-deficiency disorders.

DOI： 10.1016/j.dnarep.2021.103192

ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation. Reviewed International coauthorship International journal

Yana van der Weegen, Klaas de Lint, Diana van den Heuvel, Yuka Nakazawa, Tycho E T Mevissen, Janne J M van Schie, Marta San Martin Alonso, Daphne E C Boer, Román González-Prieto, Ishwarya V Narayanan, Noud H M Klaassen, Annelotte P Wondergem, Khashayar Roohollahi, Josephine C Dorsman, Yuichiro Hara, Alfred C O Vertegaal, Job de Lange, Johannes C Walter, Sylvie M Noordermeer, Mats Ljungman, Tomoo Ogi, Rob M F Wolthuis, Martijn S Luijsterburg

Nature cell biology Vol. 23 ( 6 ) page： 595 - 607 2021.6

Language：English Publishing type：Research paper (scientific journal)

Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4CSA ubiquitin ligase. How CRL4CSA is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4CSA for optimal RNAPII ubiquitylation. Drug-genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.

DOI： 10.1038/s41556-021-00688-9