bims-replis 2025-04-13 papers

bims-replis

Biomed News

on Replisome

Issue of 2025–04–13
six papers selected by
Anna Zawada, International Centre for Translational Eye Research

Solo or in Concert: SUMOylation in Pathogenic Fungi.
Inhibition of DNA polymerase eta-mediated translesion DNA synthesis with small molecule sensitises ovarian cancer stem-like cells to chemotherapy.
Small molecules restore mutant mitochondrial DNA polymerase activity.
The evolutionary landscape of modern-day replicases and archaeo-eukaryotic primases may have giant viral interventions.
A redefined InDel taxonomy provides insights into mutational signatures.
The 12th 3R + 3C International Symposium: A Meeting for Research Into DNA Replication, Repair, and Recombination, as Well as Chromatin, Chromosomes, and the Cell Cycle.

Plant Pathol J. 2025 Apr;41(2): 140-152

Solo or in Concert: SUMOylation in Pathogenic Fungi.

You-Jin Lim, Yong-Hwan Lee.

  SUMOylation plays a pivotal role in DNA replication and repair, transcriptional stability, and stress response. Although SUMOylation is a conserved posttranslational modification (PTM) in eukaryotes, the number, type, and function of SUMOylation-associated components vary among mammals, plants, and fungi. SUMOylation shares overlapping features with ubiquitination, another well-known PTM. However, comparative studies on the interplay between these two PTMs are largely limited to yeast among fungal species. Recently, the role of SUMOylation in pathogenicity and its potential for crosstalk with ubiquitination have gained attention in fungal pathogens. In this review, we summarize recent findings on the distinct components of SUMOylation across organisms and describe its critical functions in fungal pathogens. Furthermore, we propose new research directions for SUMOylation in fungal pathogens, both independently and in coordination with other PTMs. This review aims to illuminate the potential for advancing PTM crosstalk research in fungal systems.

Keywords:  PTMs crosstalk; pathogenic fungi; post-translational modifications (PTMs); small ubiquitin-like modifier (SUMO); ubiquitin

DOI:  https://doi.org/10.5423/PPJ.RW.11.2024.0180
Br J Pharmacol. 2025 Apr 07.

Inhibition of DNA polymerase eta-mediated translesion DNA synthesis with small molecule sensitises ovarian cancer stem-like cells to chemotherapy.

Subhankar Bose, Priyanka Saha, Md Tanjim Alam, Bilash Chatterjee, Mrinmoy Sarkar, Amit Kumar Dixit, Deepak Kumar, Rakesh Kumar Pathak, Prem Prakash Tripathi, Amit Kumar Srivastava.

   BACKGROUND AND PURPOSE: Chemoresistance and tumour relapse pose significant challenges in achieving successful chemotherapy outcomes. Targeting DNA polymerase eta (Pol ƞ)-mediated mutagenic translesion DNA synthesis (TLS) has emerged as a promising strategy for improving chemotherapy. However, the identification of small molecule inhibitors targeting Pol ƞ -mediated TLS with high in vivo efficacy remains a challenge.
EXPERIMENTAL APPROACH: The small molecule was identified through in silico screening. Pol η inhibitory potential of the identified small molecule was validated by a fluorescent-based reporter strand displacement assay. Flow cytometry was conducted to analyse the CD44 + CD117 + cancer stem-like cell (CSC) population and live-dead cell population. Xenograft mouse models were used to test the CSC sensitising potential.
KEY RESULTS: We screened and identified chrysin as a small-molecule inhibitor that sensitises ovarian cancer stem-like cells to cisplatin treatment by inhibiting Pol ƞ -mediated TLS. Chrysin effectively inhibits Pol ƞ expression, mitigates cancer stem-like cell enrichment and enhances cisplatin-induced cell death both in vitro and in vivo. Furthermore, chrysin treatment reduces spontaneous and cisplatin-induced mutagenesis. Pre-treatment with chrysin attenuates cisplatin-induced haematological toxicity and suppresses tumour growth in human ovarian cancer xenografts.
CONCLUSIONS AND IMPLICATIONS: These results establish chrysin as a novel class of TLS inhibitors and highlight its potential as a chemotherapy adjuvant for overcoming chemoresistance and improving treatment outcomes in ovarian cancer.

Keywords:  cancer stem‐like cells (CSCs); chemoresistance; chrysin; mutagenesis; translesion DNA synthesis (TLS)

DOI:  https://doi.org/10.1111/bph.70037
Nature. 2025 Apr 09.

Small molecules restore mutant mitochondrial DNA polymerase activity.

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

DOI: https://doi.org/10.1038/s41586-025-08856-9
Virology. 2025 Apr 02. pii: S0042-6822(25)00137-0. [Epub ahead of print]607 110524

The evolutionary landscape of modern-day replicases and archaeo-eukaryotic primases may have giant viral interventions.

Shailesh B Lad, Soumyadeep Mandal, Kiran Kondabagil.

  The viruses from the phylum Nucleocytoviricota have been a central part of the investigation to understand the evolution of viruses because of their atypically large particle size and large DNA genome encoding ORFs for protein translation, metabolism, and DNA replication and repair. Acanthamoeba polyphaga mimivirus (APMV), the founding member of the phylum, encodes a DNA-repair multifunctional PrimPol enzyme belonging to the archaeo-eukaryotic primase (AEP) superfamily. AEPs are enzymes present in all domains of life forms and viruses, and their versatile nature has been hypothesized to have aided in genomic replication and repair during evolution. The broad substrate specificity of AEPs allows them to act as primase, polymerase, and translesion synthesis polymerase (TLS). This multi-operational mode makes them a potential candidate for a primordial enzyme that could have been a part of the still inefficient ancient replication machinery. In this article, using the available sequence, biochemical, and structural information of AEPs, we explore the potential origins of modern-day replicases. In this context, we propose that AEPs, specifically PrimPols, have been central to the inception of modern-day replication machinery. Using APMV PrimPol as a representative candidate, we propose a model in which the parallel evolution of naked DNA elements, early viruses, cellular organisms, and the replication machinery might have occurred.

Keywords:  Archeo-eukaryotic primases; DNA repair; Genome replication; Mimivirus; Polymerase; PrimPol; Primase; Virus evolution

DOI:  https://doi.org/10.1016/j.virol.2025.110524
Nat Genet. 2025 Apr 10.

A redefined InDel taxonomy provides insights into mutational signatures.

Gene Ching Chiek Koh, Arjun Scott Nanda, Giuseppe Rinaldi, Soraya Boushaki, Andrea Degasperi, Cherif Badja, Andrew Marcel Pregnall, Salome Jingchen Zhao, Lucia Chmelova, Daniella Black, Laura Heskin, João Dias, Jamie Young, Yasin Memari, Scott Shooter, Jan Czarnecki, Matthew Arthur Brown, Helen Ruth Davies, Xueqing Zou, Serena Nik-Zainal.

Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect-a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.

DOI: https://doi.org/10.1038/s41588-025-02152-y
Genes Cells. 2025 May;30(3): e70018

The 12th 3R + 3C International Symposium: A Meeting for Research Into DNA Replication, Repair, and Recombination, as Well as Chromatin, Chromosomes, and the Cell Cycle.

Tsutomu Katayama, Masatoshi Fujita, Tatsuro S Takahashi.

The 12th 3R + 3C international symposium focused on cutting-edge research into the molecular mechanisms and regulatory systems of DNA replication, repair, and recombination (3R) as well as those of chromatin dynamics, chromosome architecture, and the cell cycle (3C). It also covered pioneering research into how these processes control cell growth, cell homeostasis, differentiation, development, and aging, in addition to how they contribute to diseases such as cancer, chromosomal abnormalities, and evolution of organisms. In terms of methodology, the symposium highlighted new trends in single-molecule/single-cell analysis, cryo-electron microscopy analysis, kinetic analysis of higher-order protein complexes, informatic analysis of genome dynamics, and new mathematical and theoretical analyses. Held in Fukuoka City center from November 18 to 22, 2024, this symposium attracted about 250 participants, including approximately 150 from Japan and nearly 100 from overseas. To foster mutual understanding and exchange between different fields, all the oral presentations took place in a single conference hall throughout the symposium. This format facilitated active and in-depth discussions among participants, including young researchers, graduate students, and postdoctoral fellows.

DOI: https://doi.org/10.1111/gtc.70018