Biology subjects

Klimova, A.

Publications and source records attributed to Klimova, A..

4 recordsLinked to original sources

bioRxiv2026

SAD-6/ATRX enables broad genome surveillance and defense in fungi

The chromatin remodeler ATRX and its orthologs maintain genome function by regulating repetitive DNA and dynamic chromatin, and their activities have been canonically associated with replication-independent deposition of the histone H3.3 variant. This model is difficult to reconcile with fungi, which encode ATRX orthologs but lack H3 variants that may separately support replication-coupled and replication-independent deposition. Here we show that the fungal ATRX ortholog SAD-6 instead relies on a highly divergent histone H4 variant (H4v) to mediate broad genome surveillance and defense. Deposition of H4v is strictly SAD-6-dependent and thus provides a sensitive genome-wide readout of SAD-6 activity, revealing its functions at telomeres, tRNA and rDNA loci, AT-rich DNA, artificial transgenes, decaying mobile elements, and many genic regions. We further show that SAD-6 is required for a pathway of repeat-induced point mutation (RIP) that also requires DIM-5, a conserved SUV39 methyltransferase that mediates trimethylation of histone H3 lysine-9 in heterochromatin. Together, these findings establish ATRX-like remodelers as broad regulators of genome surveillance and defense in fungi that act through a highly divergent histone H4 variant rather than H3.3. Given that RIP is proposed to recognize repetitive DNA via recombination-independent homologous pairing, the requirement for SAD-6 in RIP suggests that ATRX-like remodelers may couple DNA pairing to heterochromatin nucleation on repeats.

molecular biology↗

bioRxiv2026

Systematic functional drug testing in patient-derived models reveals ex vivo sensitivities associated with clinical outcome in rare solid tumors

Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers. Statement of SignificanceThis study presents a biopsy-compatible drug sensitivity testing platform for phenotype-based therapy stratification in rare cancers. It identifies actionable ex vivo drug responses and shows associations with clinical outcome in patients treated with screened therapies. These findings support functional testing as a complementary additional layer of stratification for therapeutic prioritization.

cancer biology↗

bioRxiv2025

How social and economic policies have affected the genome of mezcal agaves: the contrasting stories of Bacanora and Espadin

Plant domestication in Mesoamerica gave the world crops of global significance, such as maize, beans, squashes, cocoa, and cotton. Additionally, it has introduced species of regional economic importance, which still display intermediate levels of domestication, including Agave, Opuntia, columnar cacti, Amaranthus, and various ornamental species. Agaves, in particular, hold immense cultural and economic significance in Mexico and play a crucial ecological role in wild plant communities. However, current agricultural practices have negatively impacted both wild populations of agave through overexploitation and habitat destruction, as well as cultivated plants by reducing available landraces and promoting the use of homogeneous plant material. Using genomic data (RADseq) and over 50,000 SNPs, we aimed to assess how local social and political decisions may have influenced genomic diversity and differentiation in intensively managed, clonally propagated Agave angustifolia (Espadin) in the state of Oaxaca, as well as in the cultivated A. angustifolia used to produce mezcal known as Bacanora in the state of Sonora and their wild counterparts from both regions. We found evidence suggesting that Espadin recently aroused through farmer selection of a clonal lineage with desirable mezcal production attributes (i.e., hybrid vigor), apparently from a cross between genetically distinct wild populations or by hybridization between wild and cultivated varieties. Espadin samples were represented by closely related heterozygous genotypes, with considerable genetic differentiation from wild plants. On the other hand, the genomic composition of cultivated Bacanora agave apparently was influenced by a recently lifted ban (in 1992) on its cultivation and distillation, which, along with the relatively lower popularity of this beverage, allowed cultivated Bacanora agave to maintain the genetic diversity found in wild populations of the regions. We found that social and political decisions may have important impacts on crop genomic diversity and differentiation.

plant biology↗

bioRxiv2022

Genomic analyses of wild and cultivated bacanora agave (Agave angustifolia var. pacifica) reveal inbreeding, few signs of cultivation history and shallow population structure

Due to the recent increase in demand for agave-based beverages, many wild agave populations have experienced rapid decline and fragmentation; whereas cultivated plants are now managed at monocultural plantations, in some cases involving clonal propagation. We examined the relative effect of migration, genetic drift, natural selection and human activities on the genetic repertoire of Agave angustifolia var. pacifica, an agave used for bacanora (an alcoholic spirit similar to tequila) production in northwestern Mexico. We sampled 34 wild and cultivated sites and used over eleven thousand genome-wide SNPs. We found shallow genetic structure among wild samples, although, detected differentiation between coastal and inland sites. Surprisingly, no differentiation was found between cultivated and wild populations. Moreover, we detected moderate inbreeding (FIS [~] 0.13) and similar levels of genomic diversity in wild and cultivated agaves. Nevertheless, the cultivated plants had almost no private alleles and presented evidence of clonality. The overall low genetic structure in A. angustifolia var. pacifica is apparently the result of high dispersibility promoted by pollinators and possibility of clonal reproduction. Incipient cultivation history and reliance on wild seeds and plants are probably responsible for the observed patterns of high genetic connectivity and considerable diversity in cultivated samples.

plant biology↗