Research Interest
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#. The defense mechanisms managing DNA replication stress in human cells
#. The defense mechanisms managing DNA replication stress in human cells
Maintaining the stability of replication forks is important for genomic integrity. Highly proliferating cells are faced with persistent replication stresses. We study how human cells manage replication stress. We discovered the roles of ATAD5 in protecting the replication fork during replication stress: (1) ATAD5 helps the replication fork restart by facilitating fork restructuring (2019 Nature Comm.). (2) ATAD5 limits R-loop levels at replication forks (2020 Nuc. Acids Res.). Our current researches focuses on how single-strand DNA gap is managed to prevent fork cleavage.
Maintaining the stability of replication forks is important for genomic integrity. Highly proliferating cells are faced with
#. Intrinsic DNA features inducing replication stress monitored by PCNA ubiquitination
#. Intrinsic DNA features inducing replication stress monitored by PCNA ubiquitination
When DNA replication stalls by replication stress or DNA damage, PCNA is mono-ubiquitinated by RAD18 or poly-ubiquitinated by UBC13 and HLTF. Then, each type of ubiquitinated PCNA promotes translesion synthesis or template switch mode of damage bypass mechanism. After the damage bypass, the ubiquitinated PCNA is de-ubiquitinated by the USP1/UAF1 complex with the help of ATAD5 (Lee et al., 2010 J. Biol. Chem.). We study what is the source of endogenous replication stress based on PCNA ubiquitination and how it causes replication stress and genomic instability.
#. The mechanisms regulating DNA double-strand break repair in human cells
#. The mechanisms regulating DNA double-strand break repair in human cells
DNA double-strand breaks (DSBs) are one of the most harmful DNA lesions. DSBs are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). The NHEJ acts throughout the cell cycle and is potentially error-prone. HR is largely error-free, generally acts during S and G2 phases, and requires a sister chromatid as a repair template. We study how HR is regulated upon DSB formation. We discovered that proper PCNA unloading by ATAD5 is important during the early stage of HR. Our current researches focus on finding other HR candiate protiens and elucidating how those proteins regulate HR.
#. Identification of new DSBR/DDR proteins via proximity labeling
#. Identification of new DSBR/DDR proteins via proximity labeling
The overall DSBR process is well understood, but the mechanisms underlying the determination and regulation of various DSBR pathways remain unclear. Therefore, we aim to identify and investigate novel proteins involved in the DSBR process using the BioID-protein mass spectrometry approach (left). The system combines the LacI protein capable of binding to specific genomic loci (LacO repeat), the FokI nuclease, and the BioID enzyme which labels proximal proteins (right). By using the method, we plan to conduct large-scale experiments to find candidate proteins and move to further studies.
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