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9 recordsLinked to original sources
PubMed2026

R-loops and D-loops: a delicate balance in genomic stability and instability.

R-loops and D-loops are three-stranded nucleic acid structures that have emerged as central regulators of genome stability, gene expression, and DNA metabolism. R-loops form co-transcriptionally or post-transcriptionally when nascent RNA re-anneals with the template DNA strand, generating an RNA: DNA hybrid that displaces the non-template strand into a single-stranded state. These structures are enriched at CpG island promoters, transcription termination sites, and immunoglobulin class-switch regions, where they coordinate transcription regulation, chromatin remodeling, and DNA damage signaling. D-loops are formed when a single-stranded DNA segment pairs with one strand of a duplex and displaces the other, arising through context-dependent mechanisms that include RAD51- or DMC1-mediated strand invasion in homologous recombination, shelterin-assisted invasion at telomeres, and replication-coupled strand displacement at the mitochondrial DNA origin. They serve as indispensable intermediates in double-strand break repair, telomere maintenance, and mitochondrial DNA replication. Recent cryo-electron microscopy studies have resolved the stepwise RAD51-mediated strand exchange mechanism at near-atomic resolution, substantially advancing structural understanding of D-loop biogenesis. Despite their differences in molecular composition, both structures remodel Watson-Crick base pairing and, when dysregulated, are associated with replication fork stalling, transcription-replication conflicts, and aberrant recombination. This review systematically compares the structural features, formation mechanisms, regulatory networks, and biological functions of R-loops and D-loops, with emphasis on their convergent roles in safeguarding genome integrity. We further discuss rapidly evolving detection technologies and emerging therapeutic strategies targeting these structures in cancer and neurodegeneration, identifying key unresolved questions for future investigation.

Genomic Instability↗
PubMed2025

Donor transcription suppresses D-loops in cis and promotes genome stability.

DNA is a substrate for competing protein-mediated activities. Whether and how transcription and the synaptic steps of recombination collide or are coordinated has not been investigated. Here, using a controlled break induction system and physical detection of D-loop DNA joint molecules in S. cerevisiae, we show that donor transcription by RNA polymerase II strongly and acutely suppresses D-loops in cis. The extent of this suppression depends on the orientation of transcription, suggesting the preferential usage of one end for the repair of DNA break in transcribed regions. Transcription-mediated D-loop suppression does not rely on endogenous transcription factors, the RNA product, or RNA:DNA hybrids. It is independent of, and can be more potent than the conserved trans D-loop-disruption factors Sgs1-Top3-Rmi1BLM-TOPO3α-RMI1/2, Mph1FANCM, and Srs2. This transcription-mediated control promotes genome maintenance by inhibiting ectopic recombination and multi-invasion-induced rearrangements, while authorizing allelic inter-homolog repair. These findings reveal the prioritization between two universal DNA-dependent processes and its role in promoting genome stability.

Genomic Instability↗
PubMed2026

Whole mitogenome profile of Pelung and Sentul chickens to reveal potency of Indonesian livestock genetic resources.

Native chickens are essential genetic resources in Indonesia, providing economic, cultural, and nutritional value with strong adaptability to local environments. Among these native chickens, Sentul and Pelung are recognized as national genetic resources due to dual-purpose and ornamental traits, respectively, but their whole mitogenome characterization remains limited. Therefore, this study aimed to assemble and analyze the whole mitogenome of Sentul and Pelung chickens as well as perform a comparison with 35 additional genomes from domestic chickens and jungle fowls across Asia. The experiment was carried out using next-generation sequencing and bioinformatics-based genome assembly and analysis. The results showed that both Sentul and Pelung genomes were 16,784 bp in length and contained the typical mitochondrial gene composition, including 13 protein-coding genes (PCGs), 22 transfer ribonucleic acids (tRNAs), two ribosomal ribonucleic acids (rRNAs), and a control region (D-loop). Furthermore, comparative analysis identified five single-nucleotide polymorphisms (SNPs) distinguishing the two breeds, located in ND1, COX1, COX2, ND4, and the D-loop region. Phylogenetic reconstruction based on whole mitochondrial sequences showed that Sentul and Pelung chickens belong to haplogroup D, alongside other native breeds and red jungle fowls from Indonesia and the Philippines.

Genetic diversity↗
PubMed2025

Phosphoregulation of RAD51AP1 function in homology-directed repair.

Homology-directed DNA repair (HDR) is critical for genome stability and tumor suppression. HDR is initiated by the RAD51 single-stranded (ss)DNA nucleoprotein filament which conducts the homology search and invades a homologous DNA template, creating a displacement-loop (D-loop). The RAD51 filament is assisted in these processes by several proteins. One such protein is RAD51-Associated-Protein 1 (RAD51AP1) which binds DNA and RNA and directly interacts with RAD51. Of note, RAD51AP1 overexpression is associated with poor prognosis in several different cancer types. Here, we show that RAD51AP1 activity is regulated by phosphorylation. RAD51AP1 bearing S277/282A mutations is more proficient in the stimulation of D-loop formation than wild type RAD51AP1 or phosphomimetic RAD51AP1-S277/282D. In EMSAs, RAD51AP1 with S277/282A mutations more avidly binds ssDNA, double-stranded (ds)DNA, and the nucleosome core particle than wild type RAD51AP1 or RAD51AP1-S277/282D. In cells, RAD51AP1-S277/282A confers no rescue of RAD51AP1 deficiency in toxicity tests and DNA replication assays. In contrast, RAD51AP1-S277/282D fully rescues RAD51AP1 deficiency. We provide evidence that RAD51AP1-S277 is a CDK2 target and propose a model in which RAD51AP1-S277/282 phosphorylation ensures RAD51AP1 flexibility for dynamic engagement in consecutive steps of the HDR reaction. Our results provide new mechanistic insights into RAD51AP1 regulation by a CDK.

CDK1/2↗
PubMed2026

Mitochondrial DNA in lung cancer: From biology to clinical implications.

Mitochondrial DNA (mtDNA) is emerging as a relevant component of the molecular landscape in non-small cell lung cancer (NSCLC). Due to its inherent vulnerability to environmental carcinogens, the mitochondrial genome accumulates alterations-such as D-loop and Electron Transport Chain variants- increasingly identified as potential mediators of tumor development and metabolic shifts. Recent findings highlight potential clinical applications of mtDNA. In diagnostics, emerging models based on cf-mtDNA fragmentomics and tRNA-derived fragments have shown promising capabilities for early-stage diagnosis. Prognostically, somatic variants in Complex I and specific mitochondrial lncRNA signatures have been evaluated as independent indicators of overall survival and metastatic risk. Furthermore, mitochondrial mass may potentially support chemotherapy election. Additionally, horizontal transfer of mitochondria to tumor-infiltrating lymphocytes offers a novel framework for understanding resistance to immunotherapy. While these preliminary results provide a promising roadmap for molecular stratification, their integration into routine practice remains a goal that requires further prospective validation in larger, multi-ethnic cohorts to ensure reproducibility and to distinguish functional drivers from passenger variants. Collectively, these emerging findings suggest that mtDNA analysis represents a valuable complementary approach to precision oncology in lung cancer.

Humans↗
PubMed2023

The complete mitogenome of Paratanakia chii (Cypriniformes; Cyprinidae).

Paratanakia chii is a bitterling fish of the genus Paratanakia, subfamily Acheilognathinae and family Cyprinidae. The mitochondrial DNA sequence of P. chii is reported in this paper. The complete mitochondrial genome of P. chii is 16,575 bp in length, including 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and 1 displacement loop (D-loop). The genome sequence is consistent with those of most other carp. The majority of PCGs have AT- (Met) start codons and TA- end codons. The A + T contents of the genome, PCGs, transfer RNAs (tRNAs), and ribosomal RNAs (rRNAs) are 56.92%, 58.07%, 56.34%, and 54.21%, respectively. Phylogenetic analysis showed that P. chii is most closely related to Tanankia himantegus. These data will benefit relative ecological and phylogenetic studies.

Acheilognathinae↗
PubMed2026

An immune-associated mitochondrial DNA variant with sex differences reveals a putative novel microprotein called MASL.

The use of mitochondrial wide association studies (MiWAS) to link mitochondrial DNA variants (mtSNPs) to phenotypes of interest has uncovered important connections between mitochondrial genes and human health. The recent introduction of a re-annotated mitochondrial genome that accounts for small open reading frames (sORFs) with protein coding potential suggests the existence of mitochondrial-derived microproteins, many of which remain uncharacterized. Thus, considering the re-annotated mitochondrial genome when conducting genomic analyses such as MiWAS facilitates the mapping of mtSNPs back to microprotein-encoding sORFs and uncovers interactions between mitochondrial microproteins and biological systems. Here, we employ MiWAS of venous blood samples from the Health and Retirement Study (HRS) and identify a mtSNP associated with sex-specific changes to immune composition. After accounting for re-annotation, we map the identified mtSNP back to a sORF that encodes a novel microprotein, termed MASL (Mitochondrial Associated Small d-Loop peptide). Complementary phenome-wide association studies (PheWAS) in HRS and and UK Biobank confirm interactions between this mtSNP and immune phenotypes of interest, and our targeted RNA-Seq method (mitoSNP-seq) elucidates sex-differences in gene expression and functional pathways potentially altered by this mtSNP that may be relevant to the associated microprotein. Early characterization of the MASL microprotein shows sex-differences in circulating MASL levels in human plasma, and sex-specific interactions when comparing male and female mice treated with synthesized MASL. Together, the results of this study not only contribute to our understanding of mitochondrial dynamics in immunity, but also provide early characterization of a novel mitochondrial-derived microprotein with sex-specific modulatory effects.

Genomics↗
PubMed2024

Questioning inbreeding: Could outbreeding affect productivity in the North African catfish in Thailand?

The North African catfish (Clarias gariepinus) is a significant species in aquaculture, which is crucial for ensuring food and nutrition security. Their high adaptability to diverse environments has led to an increase in the number of farms that are available for their production. However, long-term closed breeding adversely affects their reproductive performance, leading to a decrease in production efficiency. This is possibly caused by inbreeding depression. To investigate the root cause of this issue, the genetic diversity of captive North African catfish populations was assessed in this study. Microsatellite genotyping and mitochondrial DNA D-loop sequencing were applied to 136 catfish specimens, collected from three populations captured for breeding in Thailand. Interestingly, extremely low inbreeding coefficients were obtained within each population, and distinct genetic diversity was observed among the three populations, indicating that their genetic origins are markedly different. This suggests that outbreeding depression by genetic admixture among currently captured populations of different origins may account for the low productivity of the North African catfish in Thailand. Genetic improvement of the North African catfish populations is required by introducing new populations whose origins are clearly known. This strategy should be systematically integrated into breeding programs to establish an ideal founder stock for selective breeding.

Animals↗
PubMed2026

Inference of Genetic Structure and the Process of Population Formation in Nepalese Native Goats Using Uniparental and Genome-Wide Markers.

Nepal is a small, landlocked country with marked elevational variation from the Terai plains to the Himalayas. Here, four indigenous goat populations (Chyangra, Sinhal, Khari, and Terai) are raised at different elevations. This study aimed to clarify the genetic structure of these populations and how they are formed and propagated across the Himalayan region. We analyzed 136 Nepalese goats using mitochondrial (mt) DNA D-loop and sex-determining region Y (SRY) 3'-untranslated region (UTR) sequences, as well as 50 K SNP array data. The mtDNA haplogroups D (0.162) and G (0.03) were detected only in Chyangra, whereas haplogroup B was predominant in Sinhal (0.42), followed by Khari (0.260). Regarding SRY haplotypes, Y2B was detected in all populations, whereas Y1AB (0.42) was found only in Chyangra. Genome-wide SNP analysis showed that Chyangra was genetically related to Tibetan and Central Asian goats, while Terai resembled South Asian goats. Interestingly, Sinhal formed a distinct cluster, whereas Khari exhibited an admixed genetic structure. These findings suggest that Nepalese goats originate from at least three ancestral lineages and that an additional migration route may have existed through the southern Himalayas.

50K SNP↗