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Results for “Germline mutagenesis”

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PubMed2026

MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.

SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution.

Animals↗

PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗

PubMed2026

Biochemical, structural and mutational landscapes of base excision repair enzymes and cancer: from atomic resolution to tumor signatures.

PURPOSE: Base excision repair (BER) is the predominant pathway for repairing non‑bulky oxidized and alkylated DNA base lesions, and its fidelity depends on the coordinated action of lesion‑specific DNA glycosylases and downstream repair enzymes. This review aims to summarize recent structural, biochemical, and genomic insights into three base excision repair enzymes, MUTYH DNA glycosylase, NTHL1 DNA glycosylase, and DNA polymerase β. CONCLUSION: This review outlines how MUTYH, NTHL1 and DNA polymerase β protect the genome from mutagenesis, highlights major germline variants associated with disease, and synthesizes the current knowledge on the characteristic single base substitution (SBS) mutational signatures that occur when these repair enzymes are dysfunctional.

Base excision repair↗

PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗

PubMed2026

Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesis.

UNLABELLED: Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts, but disease can progress to myelofibrosis or acute myeloid leukemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of hematopoietic colonies revealed age-appropriate polyclonal hematopoiesis in triple-negative essential thrombocythemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C > G mutations following azacitidine and characteristic T > A/T > G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate that progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis. SIGNIFICANCE: Longitudinal whole-genome sequencing shows MPN progression is genomically encoded years before clinical transformation, with distinct evolutionary routes to leukemia and MF. It identifies DNA mutagenesis associated with HC and 5-azacitidine, suggests some triple-negative cases are nonclonal, and supports serial clinical genomic monitoring for improved risk stratification and long-term management. See related commentary by Agarwal and Sankaran, p. 1724.

Humans↗

PubMed2025

Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature.

Mutations reflect the net effects of myriad types of damage, replication errors, and repair mechanisms, and thus are expected to differ across cell types with distinct exposures to mutagens, division rates, and cellular programs. Yet when mutations in humans are decomposed into a set of "signatures", one single base substitution signature, SBS5, is present across cell types and tissues, and predominates in post-mitotic neurons as well as male and female germlines [1-3]. The etiology of SBS5 is unknown. By modeling the processes by which mutations arise, we infer that SBS5 is the footprint of errors in DNA synthesis triggered by distinct types of DNA damage. Supporting this hypothesis, we find that SBS5 rates increase with signatures of endogenous and exogenous DNA damage in cancerous and non-cancerous cells and co-vary with repair rates along the genome as expected from model predictions. These analyses indicate that SBS5 captures the output of a "funnel", through which multiple sources of damage result in a similar mutation spectrum. As we further show, SBS5 mutations arise not only from translesion synthesis but also from DNA repair, suggesting that the signature reflects the occasional, shared use of a polymerase.

Journal Article↗

PubMed2026

Phosphorylation of BigH1 regulates its expression pattern and promotes embryonic development.

Metazoan genomes typically encode several linker histone variants, often expressed in a tissue- or developmental stage-specific manner. The Drosophila melanogaster genome contains only two linker histone variants: H1 is present in somatic cells, while BigH1 substitutes H1 in the germline and early embryos. In the early stages of embryogenesis, BigH1 is replaced by H1 in the chromatin of somatic cells, contributing to the initiation and maintenance of the zygotic gene expression program. Nevertheless, the molecular mechanism of this exchange and the possible functions of post-translational modifications of BigH1 in this process remain elusive. Here, we identify phosphorylation as a key post-translational regulator of BigH1 dynamics. Using proteomics and targeted mutagenesis of the endogenous BigH1 locus, we show that the loss of N-terminal phosphorylation results in persistent retention of BigH1 in somatic nuclei throughout embryogenesis, indicating a failure in BigH1 turnover. In contrast, disruption of C-terminal phosphorylation does not markedly affect BigH1 clearance but increases defects during early nuclear divisions and compromises embryonic development, particularly under suboptimal conditions. Together, these findings demonstrate that domain-specific phosphorylation differentially regulates BigH1 function, coordinating its early embryonic role with its subsequent removal from the chromatin.

BigH1↗

PubMed2026

Genomic Features Do Not Account for Differences in Multiple Myeloma Risk by Ancestry.

UNLABELLED: Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. SIGNIFICANCE: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

Humans↗