bims-replis 2025-07-20 papers

Nucleic Acids Res. 2025 Jul 08. pii: gkaf646. [Epub ahead of print]53(13):

A human high-fidelity DNA polymerase holoenzyme has a wide range of lesion bypass activities.

Rachel L Dannenberg, Joseph A Cardina, Helen Washington, Shijun Gao, Marc M Greenberg, Mark Hedglin.

During replication, lagging strand lesions are initially encountered by high-fidelity DNA polymerase (pol) holoenzymes comprised of pol δ and the PCNA sliding clamp. To proceed unhindered, pol δ holoenzymes must bypass lesions without stalling. This entails dNMP incorporation opposite the lesion (insertion) and the 5' template deoxynucleotide (extension). Historically, it was viewed that high-fidelity pol holoenzymes stall upon encountering lesions, activating DNA damage tolerance pathways that are ultimately responsible for lesion bypass. Our recent study of four prominent lesions revealed that human pol δ holoenzymes support insertion and/or bypass for multiple lesions and the extent of these activities depends on the lesion and pol δ proofreading. In the present study, we expand these analyses to other prominent lesions. Collectively, analyses of 10 lesions from both studies reveal that the insertion and bypass efficiencies of pol δ holoenzymes each span a complete range (0%-100%). Consequently, the fates of pol δ holoenzymes upon encountering lesions are quite diverse. Furthermore, pol δ proofreading promoted holoenzyme progression at 7 of the 10 lesions and did not deter progression at any. Altogether, the results significantly alter our understanding of the replicative capacity of high-fidelity pol holoenzymes and their functional role(s) in lesion bypass.

DOI: https://doi.org/10.1093/nar/gkaf646

Front Immunol. 2025 ;16 1600233

Beyond proofreading: POLD1 mutations as dynamic orchestrators of genomic instability and immune evasion in cancer.

Huiqing Chen, Jiayu Wei, Qi Tang, Guohui Li, Yajing Zhou, Zhen Zhu.

DNA polymerase delta (Pol δ) is a cornerstone of genomic stability, orchestrating DNA replication and repair through its catalytic subunit, POLD1. This subunit's 3'-5' exonuclease domain proofreads replication errors, ensuring fidelity. However, POLD1 mutations-particularly in this domain-disrupt this function, triggering genomic instability and a hypermutated state in cancers. This review delves into the multifaceted roles of POLD1 mutations, spotlighting their contributions to tumorigenesis and immunotherapy responses. Beyond their established link to syndromes like polymerase proofreading-associated polyposis (PPAP), these mutations unexpectedly enhance tumor immunogenicity in microsatellite-stable (MSS) tumors, previously considered largely resistant to immune checkpoint inhibitors (ICIs). By elevating tumor mutation burden and generating unique mutational signatures (e.g., SBS10d), POLD1 mutations sensitize MSS tumors to ICIs, challenging the dominance of microsatellite instability (MSI) as an immunotherapy predictor. Integrating structural insights, molecular mechanisms, and clinical data, this review positions POLD1 mutations as both a driver of cancer progression and a promising biomarker, redefining therapeutic possibilities in precision oncology.

Keywords: DNA polymerase delta; POLD1 mutation; cancer; genomic instability; immunotherapy

DOI: https://doi.org/10.3389/fimmu.2025.1600233

Cytogenet Genome Res. 2025 Jul 17. 1-14

Fork Stalling and Template Switching in a Complex der(6)dn with Duplication of 6q24.3qter and 6p25.3: A Case Report.

Thania Alejandra Aguayo-Orozco, Ma Guadalupe Domínguez-Quezada, Horacio Rivera, Luis E Figuera, Eduardo Esparza-García, Luis Ángel Núñez-García, Elvira Garza-González, Carlos Córdova-Fletes.

INTRODUCTION: Partial trisomy of the 6q24qter region is a rare chromosomal disorder characterized by variable clinical features and poorly understood mechanistic origins.
CASE PRESENTATION: We describe a de novo complex der(6) chromosome in a patient with features consistent with partial 6q trisomy syndrome, including congenital heart disease, growth restriction, developmental delay, and dysmorphic traits. Molecular Findings. Whole-genome sequencing (WGS) identified duplications of 1.5 Mb on 6p25.3 and 23.3 Mb on 6q24.3-qter. While the 6p duplication appears benign, the phenotype is likely driven by dosage-sensitive 6q genes (ARID1B, TAB2, QKI) and possible additive effects from other duplicated genes. No parental pericentric inversion was detected by classical or molecular cytogenetics, and WGS revealed no inversion-associated breakpoints. Instead, chimeric (q-/q+) and truncated reads at the 6q junction support a replication-based origin, such as reversed template switching. FISH confirmed direct insertion of the 6q segment into 6p25.3, without a del/dup pattern typical of inversion-derived recombinants. Notably, WGS detected no direct 6p-6q junction reads, but identified chimeric 6p-15q-6q reads with 2-bp microhomologies, suggesting that chromosome 15 transiently mediated the rearrangement. Interspersed telomeric sequences and flanking Alu elements were also found at both breakpoints.
CONCLUSION: Altogether, these findings support a model in which replication fork stalling and template switching-potentially facilitated by telomere dynamics and repetitive elements-led to the formation of a recombinant-like der(6) chromosome. This case highlights the mechanistic complexity of structural rearrangements and the role of replication-based errors in shaping human genomic variation.

DOI: https://doi.org/10.1159/000547454