Biology subjects

Zilio, N.

Publications and source records attributed to Zilio, N..

3 recordsLinked to original sources

bioRxiv2026

RepliCNN: High-resolution inference of the DNA replication program from strand-specific 3' DNA end sequencing

During S phase, the genome is replicated in a tightly regulated spatiotemporal order described as DNA replication timing (RT). Discontinuous lagging-strand synthesis produces Okazaki fragments whose strand-specific distribution reflects replication dynamics. Here, we present RepliCNN, a deep learning framework based on one-dimensional convolutional neural networks to predict RT from Okazaki fragment distributions obtained from strand-specific 3' DNA end sequencing methods such as GLOE-Seq, TrAEL-seq, or OK-Seq. RepliCNN also automatically annotates replication origins, termination zones, replication fork directionality, and origin efficiency genome-wide from a single dataset. Benchmarking on public and in-house human and yeast datasets using leave-one-chromosome-out cross-validation demonstrates high predictive accuracy in both wild-type and perturbation experiments, enabling comprehensive analyses of replication dynamics from strand-specific DNA 3' end sequencing data. HighlightsO_LIRepliCNN enables integrated analysis of replication timing, fork directionality and replication features from strand-specific 3' DNA end sequencing data. C_LIO_LIHigh-resolution replication dynamics can be inferred from a single experiment, bypassing complex multi-fraction labelling approaches. C_LIO_LIThe framework generalizes across experimental protocols, datasets, and species. C_LIO_LIThis enables cost-effective comparative analysis of replication programs across biological conditions. C_LI

bioinformatics↗

bioRxiv2023

Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes

Most genotoxic anticancer agents fail in tumors with intact DNA repair. Therefore, trabectedin, a unique agent more toxic to cells with active DNA repair, specifically transcription-coupled nucleotide excision repair (TC-NER), provides new therapeutic opportunities. To unlock the potential of trabectedin and inform its application in precision oncology, a full mechanistic understanding of the drugs TC-NER-dependent toxicity is needed. Here, we determined that abortive TC-NER of trabectedin-DNA adducts forms persistent single-strand breaks (SSBs) as the adducts block the second of the two sequential NER incisions. We mapped the 3-hydroxyl groups of SSBs originating from the first NER incision at trabectedin lesions, recording TC-NER on a genome-wide scale. We showed that trabectedin-induced SSBs primarily occur in transcribed strands of active genes and peak near transcription start sites. Frequent SSBs were also found outside gene bodies, connecting TC-NER to divergent transcription from promoters. This work advances the use trabectedin for precision oncology and for studying TC-NER and transcription.

molecular biology↗

bioRxiv2022

The Nse5/6-like SIMC1-SLF2 Complex Localizes SMC5/6 to Viral Replication Centers

The human SMC5/6 complex is a conserved guardian of genome stability and an emerging component of antiviral responses. These disparate functions likely require distinct mechanisms of SMC5/6 regulation. In yeast, Smc5/6 is regulated by its Nse5/6 subunits, but such regulatory subunits for human SMC5/6 are poorly defined. Here, we identify a novel SMC5/6 subunit called SIMC1 that contains SUMO interacting motifs (SIMs) and an Nse5-like domain. We isolated SIMC1 from the proteomic environment of SMC5/6 within polyomavirus large T antigen (LT)-induced subnuclear compartments. SIMC1 uses its SIMs and Nse5-like domain to localize SMC5/6 to polyomavirus replication centers (PyVRCs) at SUMO-rich PML nuclear bodies. SIMC1s Nse5-like domain binds to the putative Nse6 orthologue SLF2 to form an anti-parallel helical dimer resembling the yeast Nse5/6 structure. SIMC1-SLF2 structure-based mutagenesis defines a conserved surface region containing the N-terminus of SIMC1s helical domain that regulates SMC5/6 localization to PyVRCs. Furthermore, SLF1, which recruits SMC5/6 to DNA lesions, binds SLF2 analogously to SIMC1 and forms a distinct Nse5/6-like complex. Thus, two Nse5/6-like complexes independently regulate human SMC5/6: SIMC1-SLF2 responding to viral challenge and SLF1/2 recognizing DNA damage.

cell biology↗