Biology subjects

Subedi, U.

Publications and source records attributed to Subedi, U..

3 recordsLinked to original sources

bioRxiv2026

FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer

BRCA1 deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1/FANCM synthetic lethality in human BRCA1 deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome wide structural variation in BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome integration links newly emerged SVs to configuration dependent local transcriptional changes. Together, these findings establish FANCM as a replication stress safeguard coupling survival to restraint of structural genome evolution.

cancer biology↗

bioRxiv2026

Comprehensive Analysis Reveals Adaptive DNA Repair and Replication Stress Networks in Genomically Unstable Breast Cancer

Genomic instability is a defining hallmark of breast cancer, yet the mechanisms by which tumors tolerate persistent DNA damage remain poorly understood. We performed a comprehensive, multi-cohort analysis of breast cancer datasets to define how DNA damage response (DDR) and replication stress tolerance (RST) networks are rewired in genomically unstable tumors. Using fraction of genome altered (FGA) as a chromosomal instability metric, we show that BRCA-mutant tumors exhibit elevated genomic instability coupled with increased expression of homologous recombination, Fanconi anemia, mismatch repair, base excision repair, and alternative end-joining pathways. Strikingly, heightened pathway activity correlates with increased genome alteration, supporting a model of damage tolerance rather than repair restoration. RST programs, including fork remodeling, protection, and single strand DNA gap suppression, further contribute to tumor fitness under replication stress. These adaptive states are enriched in aggressive subtypes, intensified with progression, and associate with pathway-specific mutational burden. Co-occurrence and mutual exclusivity mapping uncovered non-random subtype-relevant genetic interactions states among major drivers and DDR genes, nominating context-specific synthetic lethal opportunities. Our findings identify compensatory genome-maintenance programs as central drivers of tumor resilience and highlight pathway-specific vulnerabilities for targeted therapeutic intervention.

cancer biology↗

bioRxiv2026

Successful gene editing in tetraploid alfalfa using the open-source, AI-derived OpenCRISPR-1

While CRISPR/Cas-based gene editing technologies have the potential to greatly advance crop breeding endeavours, intellectual property-related challenges can hinder the ability to move such varieties to the market. Recently, an open-access Cas enzyme derived from large language models (OpenCRISPR-1) was developed and shown to function effectively in human cells. In this study, we demonstrate the successful use of this nuclease in a polyploid plant species (Medicago sativa), with mono- or bi-allelic editing observed in 30% of genotypes bearing OpenCRISPR-1. These findings indicate that OpenCRISPR-1 holds promise to expand the use of gene editing technology in the breeding of polyploid crops.

plant biology↗