Nucleotide insufficiency induced by p53 deficiency leads to replication stress driving genomic instability DOI

Wisam Zaatra,

George Philippos, Petr Smirnov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Abstract P53 plays a critical role in preventing DNA damage accumulation by activating repair processes, inducing cell cycle arrest, or triggering apoptosis. Loss of p53 leads to replication stress and genomic instability, yet the mechanisms underlying these effects their contribution catastrophic events like chromothripsis remain poorly understood. Using patient-derived fibroblasts with germline variants that spontaneously undergo chromothripsis, as well p53-downregulated fibroblasts, we discovered loss disrupts balance between nucleotide consumption production through increasing transcription decreasing biosynthesis, respectively. This imbalance results insufficient pools, leading stress. We further showed this triggers telomere dysfunction micronuclei formation, ultimately causing chromothripsis. Supplementing nucleosides inhibiting rescued instability. also observed emergence dominant chromothriptic clones, which exhibited normal replication, stabilization, extrachromosomal circular structures, highlighting features for clonal selection expansion.

Language: Английский

Exploring the Potential of Optical Genome Mapping in the Diagnosis and Prognosis of Soft Tissue and Bone Tumors DOI Open Access

Alejandro Berenguer-Rubio,

Esperanza Such, Neus Torres Hernández

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2820 - 2820

Published: March 20, 2025

Sarcomas are rare malignant tumors of mesenchymal origin with a high misdiagnosis rate due to their heterogeneity and low incidence. Conventional diagnostic techniques, such as Fluorescence In Situ Hybridization (FISH) Next-Generation Sequencing (NGS), have limitations in detecting structural variations (SVs), copy number (CNVs), predicting clinical behavior. Optical genome mapping (OGM) provides high-resolution genome-wide analysis, improving sarcoma diagnosis prognosis assessment. This study analyzed 53 samples using OGM. Ultra-high molecular weight (UHMW) DNA was extracted from core resection biopsies, data acquisition performed the Bionano Saphyr platform. Bioinformatic pipelines identified variations, comparing them known alterations for each subtype. OGM successfully 62.3% samples. Diagnostic-defining were found 95.2% cases, refining diagnoses revealing novel oncogenic tumor suppressor gene alterations. The challenges included extraction quality issues some tissue Despite these limitations, proved be powerful predictive tool bone soft sarcomas, surpassing conventional methods resolution scope, enhancing understanding genetics, enabling better patient stratification personalized therapies.

Language: Английский

Citations

0
Nucleotide insufficiency induced by p53 deficiency leads to replication stress driving genomic instability DOI

Wisam Zaatra,

George Philippos, Petr Smirnov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 18, 2025

Abstract P53 plays a critical role in preventing DNA damage accumulation by activating repair processes, inducing cell cycle arrest, or triggering apoptosis. Loss of p53 leads to replication stress and genomic instability, yet the mechanisms underlying these effects their contribution catastrophic events like chromothripsis remain poorly understood. Using patient-derived fibroblasts with germline variants that spontaneously undergo chromothripsis, as well p53-downregulated fibroblasts, we discovered loss disrupts balance between nucleotide consumption production through increasing transcription decreasing biosynthesis, respectively. This imbalance results insufficient pools, leading stress. We further showed this triggers telomere dysfunction micronuclei formation, ultimately causing chromothripsis. Supplementing nucleosides inhibiting rescued instability. also observed emergence dominant chromothriptic clones, which exhibited normal replication, stabilization, extrachromosomal circular structures, highlighting features for clonal selection expansion.

Language: Английский

Citations

0