PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability

Ma, Shuai; Cao, Cheng; Che, Shiyou; Wang, Yuejiao; Su, Dongxue; Liu, Shuai; Gong, Wenchen; Liu, Ling; Sun, Jixue; Zhao, Jiang; Wang, Qian; Song, Nan; Ge, Tong; Guo, Qiushi; Tian, Shanshan; Chen, Charlie Degui; Zhang, Tao; Ju, Wang; Ding, Xiang; Yang, Fuquan; Ying, Guoguang; Yang, Jie; Zhang, Kai; Zhu, Yi Dan; Yao, Zhi; Yang, Na; Shi, Lei

doi:10.1126/sciadv.abf7684

Cited by 15 publications

(23 citation statements)

References 70 publications

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“…Moreover, we performed single‐cell regulatory network inference and clustering (SCENIC) analysis to systemically infer TF‐driven regulons of each tumor cell subpopulation. As shown in Figure 5E and Table S6, HB1–Pro‐like1 cells were highly enriched of multiple MYC‐associated TF regulons (MYC/HMGA1/HMGA2/MXD1), HB1–Pro‐like2 cells were highly enriched of cell cycle‐associated TF regulons (MYBL1/MYBL2/E2F1/TFDP1), HB1–Pro‐like3 cells were highly enriched of cholangiocyte‐associated TF regulons (JUN/TFF3/KLF5),19,21 HB1–Pro‐like4 cells were moderately enriched of hepatocyte‐ and cell cycle‐associated TF regulons (HNF4A/MYBL2/E2F1/TFDP1), HB2–mesenchyme‐like cells were highly enriched of WNT‐ and mesenchymal cell‐associated TF regulons (CTNNB1/TCF3/TCF4/TCF7/TWIST1), HB3–hepatocyte‐like cells were highly enriched of hepatocyte‐associated TF regulons (HNF1A/HNF4A/ESR1), and HB4 cells were enriched of DNA damage repair‐associated TF regulons (IRF9/AR/PPARGC1A/PHF8) 22–25. The expression analysis further confirmed a correlation between TF regulon enrichment and transcript levels (Figure S9D).…”

Section: Resultsmentioning

confidence: 95%

Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Huang

Lü

et al. 2023

Hepatology

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Background and Aims: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single‐cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. Approach and Results: Single‐cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single‐cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post–neoadjuvant chemotherapy tumor samples. A single‐cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic‐targeted therapeutic strategy against the CSC‐like HB1–Pro‐like1 subpopulation and its related high‐risk “Pro‐like1” subtype of HB. Conclusions: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single‐cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

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Section: Resultsmentioning

confidence: 95%

Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Huang

Lü

et al. 2023

Hepatology

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“…Replication stress results in KDM7B phosphorylation and dissociation from topoisomerase IIβbinding protein 1 (TOPBP1). Consequently, hypomethylated TOPBP1 facilitates RADiation-sensitive 9-binding to chromatin to fully activate ATR and thus safeguard the genome and protect cells against replication stress (Feng et al, 2020;Ma et al, 2021). Although many studies have observed the role of KDM7B in transcription silencing, further studies are needed to elaborate on the role of KDM7B in the DDR.…”

Section: Histone H4 Lysine20 Demethylationmentioning

confidence: 99%

Biological function and regulation of histone 4 lysine 20 methylation in DNA damage response

Kohi

Feng

Tian

et al. 2022

GENOME INSTAB. DIS.

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Cells are often under attack from various DNA-damaging agents. Accurate repair is required to protect cells from the genome instability induced by DNA lesions. DNA damage response (DDR) signaling involves sensitizing, transmitting, and repairing different types of damage within chromatin complexes. Chromatin is a highly ordered complex packed with repeating units of nucleosomes and linker DNA sequences. Chromatin structure, gene transcription, and various biological processes are regulated by histone post-translational modifications (PTMs), including acetylation, methylation, phosphorylation, and ubiquitylation. Of these, the involvement of lysine methylation, regulated by numerous lysine methyltransferases and demethylases, in the DDR has been extensively explored. In particular, histone 4 lysine 20 methylation is one of the most essential histone PTMs for biological processes and ensures genome integrity. In this review, we summarize the dynamics and modulations of histone lysine methylation during the DDR. We also comprehensively describe the functions, mechanisms, and regulation of H4K20 methylation and its modifying enzymes in response to DNA damage.

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“…10 Recent research has also discovered that Topbp1 can reduce methylation levels by binding to plant homeodomain finger protein 8 (PHF8) through the C-terminal BRCT7/8. 11 PHF8 is a histone demethylase that recognizes histone H3 lysine 4 (H3K4) methylation marks through its N-terminal PHD domain. Additionally, its C-terminal Jumonji C domain facilitates demethylation reactions of various lysine residues on histones.…”

Section: ■ Introductionmentioning

confidence: 99%

“…At this stage, low-methylated Topbp1 is recruited and bound by RAD9. 11 Eventually, ATR binds to Topbp1, resulting in the formation of a complete complex and activation of ATR (Figure 1). 18,19 Under physiological conditions, PHF8 undergoes phosphorylation and dissociates from Topbp1 in response to signals from cellular replication stress.…”

Section: ■ Introductionmentioning

confidence: 99%

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Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

Yuan,

Liang,

2024

ACS Omega

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DNA topoisomerase 2-binding protein 1 (Topbp1) plays a crucial role in activating the ataxia-telangiectasia mutated and rad3-related (ATR) complex to initiate DNA damage repair responses. For this process to occur, it is necessary for PHF8 to dissociate from Topbp1. Topbp1 binds to the acidic patch sequence (APS) of PHF8 through its C-terminal BRCT7/8 domain, and disrupting this interaction could be a promising strategy for cancer treatment. To investigate the dissociation process and binding pattern of BRCT7/8-PHF8, we employed enhanced sampling techniques, such as steered molecular dynamics (SMD) simulations and accelerated molecular dynamics (aMD) simulations, along with self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. Our results demonstrate that the dissociation of PHF8 from BRCT7/8 starts from the N-terminus, leading to the unfolding of the N-terminal helix. Additionally, we identified critical residues that play a pivotal role in this dissociation process. These findings provide valuable insights into the disassociation of PHF8 from BRCT7/8, which could potentially guide the development of novel drugs targeting Topbp1 for cancer therapy.

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PHF8-promoted TOPBP1 demethylation drives ATR activation and preserves genome stability

Cited by 15 publications

References 70 publications

Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Single‐cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma

Biological function and regulation of histone 4 lysine 20 methylation in DNA damage response

Insights into the Dissociation Process and Binding Pattern of the BRCT7/8-PHF8 Complex

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