Article
Multidisciplinary Sciences
Kavi P. M. Mehta, Vaughn Thada, Runxiang Zhao, Archana Krishnamoorthy, Micheal Leser, Kristie Lindsey Rose, David Cortez
Summary: Replication-coupled DNA repair and damage tolerance mechanisms help overcome replication stress challenges and complete DNA synthesis. Different pathways, such as fork reversal, translesion synthesis, and repriming, are used and regulated in response to varying replication stresses.
Article
Genetics & Heredity
Cezary Cybulski, Neda Zamani, Wojciech Kluzniak, Larissa Milano, Dominika Wokolorczyk, Klaudia Stempa, Helena Rudnicka, Shiyu Zhang, Maryam Zadeh, Tomasz Huzarski, Anna Jakubowska, Tadeusz Debniak, Marcin Lener, Marek Szwiec, Pawel Domagala, Amir Abbas Samani, Steven Narod, Jacek Gronwald, Jean-Yves Masson, Jan Lubnski, Mohammad R. Akbari
Summary: Through whole-exome sequencing of a founder population in Poland, researchers identified a rare ATRIP gene mutation associated with breast cancer. This association was further confirmed in validation studies. Functional experiments revealed that the ATRIP mutation leads to loss of heterozygosity and genomic homologous recombination deficiency in breast cancer cells, linking DNA replication stress to breast cancer.
AMERICAN JOURNAL OF HUMAN GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Andreas Panagopoulos, Matthias Altmeyer
Summary: Cell cycle checkpoints play a crucial role in ensuring ordered progression between cell cycle phases, signaling cell stress and DNA damage, and halting cell cycle progression in the face of severe problems. Recent research indicates that cells respond to natural challenges such as replication impediments with more subtle and sophisticated mechanisms, utilizing fine-tuned deceleration and brake release controlled by ATR and CHK1. This reveals a more flexible adaptation of the cell cycle program to changing conditions.
TRENDS IN BIOCHEMICAL SCIENCES
(2021)
Article
Multidisciplinary Sciences
Yudong Zhang, Lingli Yuan
Summary: This study elucidates the regulatory mechanism of FLT3-ITD on CHK1 and reveals the correlation between high CHK1 level and lower survival rates in AML patients. Knockdown of CHK1 enhances the sensitivity of AML cells to epigenetic inhibitors, suggesting a potential therapeutic strategy for FLT3-ITD+AML.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Cristina Gonzalez-Garrido, Felix Prado
Summary: Cdc7 and Dbf4 form a complex that is essential for DNA replication initiation. During replication stress, late origins are inhibited to prevent cell cycle progression. Studies have shown that Cdc7 not only plays a role in origin activation, but also in the DNA damage response. Therefore, understanding the spatiotemporal regulation of DDK is important for better understanding these processes.
Article
Cell Biology
Xinyu Yang, Xinjie Chen, Shaosen Zhang, Wenyi Fan, Ce Zhong, Tianyuan Liu, Guoyu Cheng, Liang Zhu, Qingyi Liu, Yiyi Xi, Wen Tan, Dongxin Lin, Chen Wu
Summary: This study investigates the mechanisms driving radioresistance in esophageal squamous-cell carcinoma (ESCC) by analyzing patient-derived xenografts (PDXs). The findings reveal the enrichment of collagen type 1 (Col1) derived from cancer-associated fibroblasts (CAF) and CXCL1 derived from tumor cells in non-responsive PDXs. Col1 not only promotes radioresistance by enhancing DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo.
Article
Biochemistry & Molecular Biology
Diletta Ciardo, Olivier Haccard, Hemalatha Narassimprakash, David Cornu, Ida Chiara Guerrera, Arach Goldar, Kathrin Marheineke
Summary: This study demonstrates that Plk1 plays a crucial role in regulating replication origin firing during the non-challenged S phase through interactions with various factors. By analyzing the effects of Plk1 depletion on replication fork density and initiation frequency, as well as its interaction with Rif1 and other firing factors, the study provides insights into how Plk1 controls the activation of origins at the level of large chromatin domains in vertebrates.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Benjamin R. Stromberg, Mayank Singh, Adrian E. Torres, Amy C. Burrows, Debjani Pal, Christine Insinna, Yosup Rhee, Andrew S. Dickson, Christopher J. Westlake, Matthew K. Summers
Summary: The deubiquitinating enzyme USP37 is required beyond S-phase entry to promote the efficiency and fidelity of replication. Depletion of USP37 leads to increased replication stress and DNA damage, reduced cellular proliferation, and increased sensitivity to agents that induce replication stress. USP37 stabilizes checkpoint kinase 1 to ensure proper function and plays a crucial role in regulating cell proliferation and genome stability.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Lorenza Garribba, Giuseppina De Feudis, Valentino Martis, Martina Galli, Marie Dumont, Yonatan Eliezer, Rene Wardenaar, Marica Rosaria Ippolito, Divya Ramalingam Iyer, Andrea E. Tijhuis, Diana C. J. Spierings, Michael Schubert, Silvia Taglietti, Chiara Soriani, Simon Gemble, Renata Basto, Nick Rhind, Floris Foijer, Uri Ben-David, Daniele Fachinetti, Ylli Doksani, Stefano Santaguida
Summary: Chromosomal instability (CIN) is a common form of genome instability and is closely associated with cancer. Aneuploidy, a state of karyotype imbalance, can trigger CIN and result in genetically diverse cells with chromosomal abnormalities. Cycling aneuploid cells have lower karyotype complexity compared to arrested ones, but both show increased expression of DNA repair signatures. Interestingly, highly-proliferative cancer cells also exhibit upregulation of the same signatures, which allows them to proliferate despite aneuploidy-induced CIN.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Fiifi Neizer-Ashun, Shailendra Kumar Dhar Dwivedi, Anindya Dey, Elangovan Thavathiru, William L. Berry, Susan Patricia Lees-Miller, Priyabrata Mukherjee, Resham Bhattacharya
Summary: This study characterizes the biology of KRCC1 and uncovers its involvement in the DNA damage response and cell cycle progression. KRCC1 facilitates RAD51 recombinase foci formation, regulates the CHK1-mediated checkpoint, and is required for proper S-phase progression and mitotic entry.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Jinal A. Patel, Hyungjin Kim
Summary: Accurate replication of the genome is crucial for cellular survival and tumor prevention. The DNA replication fork is susceptible to DNA lesions and damages that hinder its progression, leading to genome instability and tumorigenesis. The fork protection complex (FPC), particularly TIMELESS (TIM), plays a vital role in safeguarding the integrity of both active and stalled replication forks. Understanding TIM's multifaceted functions in DNA replication and stalled fork protection, as well as its collaboration with other genome surveillance factors, provides insights for potential therapies targeting replication vulnerability in cancer cells.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Marina Dall'Osto, Laura Pierini, Nicolas Valery, Jean-Sebastien Hoffmann, Marie-Jeanne Pillaire
Summary: The study revealed a new role of Pol kappa in controlling the stability and abundance of checkpoint kinase 1 (Chk1), where loss of Pol kappa decreases Chk1 protein levels and protects it from proteasome degradation. Additionally, the fork restart defects in Pol kappa-depleted cells can be overcome by the reexpression of Chk1.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Oncology
Nicola Lockwood, Silvia Martini, Ainara Lopez-Pardo, Katharina Deiss, Hendrika A. Segeren, Robert K. Semple, Ian Collins, Dimitra Repana, Mathias Cobbaut, Tanya Soliman, Francesca Ciccarelli, Peter J. Parker
Summary: G2 arrest is crucial for the faithful segregation of sister chromatids, and the p53-p21 signaling pathway plays an essential role in cell lines, patient-derived cells, and colorectal cancer organoids. In arrest-defective hTERT-positive cells, the PKC epsilon failsafe mechanism is engaged. In ALT-dependent cancer cells, a distinct form of p53-independent G2 arrest is mediated by BLM and Chk1.
Article
Biochemistry & Molecular Biology
Kenna Ruis, Oanh Huynh, Katrina Montales, Nina A. Barr, W. Matthew Michael
Summary: TOPBP1 is an important activator of ATR kinase that contains nine BRCT domains and an AAD domain, playing a role in ATR activation through protein-protein interactions. The delineation of TOPBP1 Junior, composed of BRCT0-2, AAD, and BRCT7 & 8, provides insight into the mechanism of ATR activation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Gijs Zonderland, Riccardo Vanzo, Sampath Amitash, Elena Martin-Doncel, Fabian Coscia, Andreas Mund, Mads Lerdrup, Jan Benada, Dominik Boos, Luis Toledo
Summary: In contrast to existing models, the TRESLIN-MTBP complex can prevent premature entry into G2 independently of ATR/CHK1 kinases in early S-phase. It acts as a monitoring system that checks the activation of replication forks and senses the rate of origin firing to prevent premature entry into G2.
Article
Multidisciplinary Sciences
Shojiro Kitajima, Wendi Sun, Kian Leong Lee, Jolene Caifeng Ho, Seiichi Oyadomari, Takashi Okamoto, Hisao Masai, Lorenz Poellinger, Hiroyuki Kato
Summary: The UTX/KDM6A gene encodes a major histone H3 lysine 27 (H3K27) demethylase and is frequently mutated in human cancers. The pharmacological inhibitor GSK-J4 induces the expression of ATF4 protein and its target genes. The inhibition of UTX partially leads to ATF4 induction, suggesting a potential role of UTX in regulating cancer formation through the HRI-ATF4 axis.
SCIENTIFIC REPORTS
(2021)
Editorial Material
Biochemistry & Molecular Biology
Masaya Oki, Hisao Masai
Summary: HP1 is a key factor for the formation of heterochromatin by binding to the methylated lysine 9 of histone H3, repressing transcription. Recent studies show that HP1 family proteins are dynamically regulated by phosphorylation during cell cycle, affecting their functions in chromosome maintenance and segregation.
JOURNAL OF BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Koutarou Nakamura, Seiichiro Sakai, Jun Tsuyama, Akari Nakamura, Kento Otani, Kumiko Kurabayashi, Yoshiko Yogiashi, Hisao Masai, Takashi Shichita, Lucas Smith
Summary: Inflammation plays a crucial role in the onset and progression of various diseases. DJ-1 functions as a DAMP and triggers inflammation when released from dead cells, and can activate TLR2 and TLR4 in infiltrating myeloid cells in the ischemic brain. Neutralizing extracellular DJ-1 suppresses cerebral post-ischemic inflammation and attenuates ischemic neuronal damage, suggesting a potential therapeutic target for tissue injuries and neurodegenerative diseases.
Article
Biochemistry & Molecular Biology
Naoko Yoshizawa-Sugata, Satoshi Yamazaki, Kaoru Mita-Yoshida, Tomio Ono, Yasumasa Nishito, Hisao Masai
Summary: Rif1 depletion alters the enhancer structure of Zscan4, leading to upregulation of 2C transcripts and potentially inhibiting endogenous Rif1 protein localization at the nuclear periphery through hetero-oligomer formation. In murine 2C embryos, most Rif1-derived polypeptides are expressed as truncated forms, likely nonfunctional, with gradual increase of the full-length form thereafter.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Takayuki Irie, Tokiko Asami, Ayako Sawa, Yuko Uno, Chika Taniyama, Yoko Funakoshi, Hisao Masai, Masaaki Sawa
Summary: By optimizing a series of furanone analogues, researchers have obtained a potent CDC7 inhibitor, with excellent kinase selectivity and oral bioavailability, demonstrating robust in vivo antitumor efficacy. This compound is currently in phase I clinical trials for the treatment of solid cancers.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Hisao Masai
Summary: This article summarizes the recent progress in DNA replication and the evolution of replication systems. It provides detailed information about the proteins involved in the replication of host chromosomes and their mechanisms of action. Additionally, it discusses the alternative modes of initiation in prokaryotes and eukaryotes.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Hao-Wen Hsiao, Chi-Chun Yang, Hisao Masai
Summary: It has been found that various biological stresses can activate Chk1, leading to DNA replication arrest and cell cycle alteration. Activation of Chk1 in S phase relies on Claspin, while in G1 phase it is mostly independent of Claspin. These findings reveal novel links between replication stress checkpoint and other biological stresses, and suggest the existence of replication-independent mechanisms of Chk1 activation in mammalian cells.
Article
Biology
Yutaka Kanoh, Masaru Ueno, Motoshi Hayano, Satomi Kudo, Hisao Masai
Summary: Rif1 overexpression leads to nuclear relocation, growth inhibition, and cell death, affecting both the S and M phases of the cell cycle. Rif1 overexpression induces chromatin relocation near the nuclear periphery, which is potentially related to growth inhibition.
LIFE SCIENCE ALLIANCE
(2023)
Article
Cell Biology
Karin Hori, Satoshi Yamazaki, Chiaki Ohtaka-Maruyama, Tomio Ono, Tomohiro Iguchi, Hisao Masai
Summary: By using Nestin-Cre, we generated mice with Cdc7 knockout in neural stem cells, which displayed severe growth retardation and impaired postnatal brain development. Cerebral cortical layer formation was impaired, while cell numbers remained unchanged. In the hypoplastic cerebellum, granule cell numbers were reduced, indicating that Cdc7 is necessary for DNA replication and cell proliferation of granule cells during mid embryonic stage. These findings demonstrate differential roles of Cdc7 in brain DNA replication/cell proliferation and suggest a potential additional role in cell migration during neural development.
Correction
Biochemistry & Molecular Biology
Hao-Wen Hsiao, Chi-Chun Yang, Hisao Masai
Article
Biochemistry & Molecular Biology
Chi-Chun Yang, Hisao Masai
Summary: Claspin plays multiple important roles in DNA replication regulation, including mediating the cellular response to replication stress, facilitating replication fork progression, and promoting initiation by recruiting Cdc7 kinase. It is also found to be involved in growth recovery from serum starvation through the activation of the PI3K-PDK1-Akt-mTOR pathway. In the absence of Claspin, cells fail to enter S phase and eventually undergo partial death in a manner dependent on ROS and p53.
MOLECULAR AND CELLULAR BIOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Youichi Tajima, Futoshi Shibasaki, Hisao Masai
Summary: The study reveals that bladder cancer cells can undergo cell fusion with bone marrow-derived MSC, resulting in fusion cells with high tumorigenicity. Fusion cells exhibit genomic instability, increased cell proliferation, and enhanced tumor formation compared to parent cells. The altered gene expression and overexpression of cytokines in fusion cells provide insights into the mechanisms underlying cell fusion-mediated tumorigenesis. The study also highlights the potential of targeting PD-L1 and utilizing cancer immunotherapy for the treatment of bladder cancer.
CANCER GENE THERAPY
(2023)
Review
Biochemistry & Molecular Biology
Sana Alavi, Hamed Ghadiri, Bahareh Dabirmanesh, Kenji Moriyama, Khosro Khajeh, Hisao Masai
Summary: DNA replication is regulated spatially and temporally during S phase, with Rif1 playing a key role in shaping 'replication domains' that dictate when and where segments of the genome are replicated. Rif1 achieves this through higher-order chromatin architecture near the nuclear membrane and recruitment of a protein phosphatase. The G4 binding activity of Rif1 is essential for replication timing regulation in fission yeast.
JOURNAL OF BIOCHEMISTRY
(2021)
