Biology subjects

Hooper, W.

Publications and source records attributed to Hooper, W..

3 recordsLinked to original sources

bioRxiv2025

APOBEC3A-Induced DNA Damage Drives Polymerase Theta Dependency and Synthetic Lethality in Cancer

APOBEC3 cytidine deaminases drive cancer evolution. There is an unmet need to target cancer cells with APOBEC3 activity. Here, we identify error-prone theta-mediated end joining (TMEJ) as the main pathway for repairing APOBEC3-induced double-strand breaks (DSBs). Using fluorescent DSB repair reporters and a novel biochemical assay, we demonstrate that APOBEC3A competes with replication protein A (RPA) for single-stranded DNA overhangs, exposing microhomologous sequences to shift DSB repair towards error-prone TMEJ. Genomic analysis of clinical tumor samples confirmed the co-occurrence and proximity between APOBEC3-induced mutational footprints, microhomology-mediated deletions (MMDs), and TMEJ-associated chromosomal instability signatures. Crucially, inhibition of DNA polymerase theta (Pol{theta}) synergizes with APOBEC3A-induced DSBs to induce synthetic lethality in vitro and in vivo. Collectively, our findings identify TMEJ as the preferred mechanism for repairing APOBEC3A-induced DSBs and establish Pol{theta} inhibition as a novel promising strategy to eliminate cancer cells with APOBEC3A activity.

cancer biology↗

bioRxiv2025

Lancet2: Improved and accelerated somatic variant calling with joint multi-sample local assembly graph

Here, we present Lancet2, an open-source somatic variant caller designed to improve detection of small variants in short-read sequencing data. Lancet2 introduces significant enhancements, including: 1) Improved variant discovery and genotyping through partial order multiple sequence alignment of assembled haplotype contigs and re-alignment of sample reads to the best supporting allele. 2) Optimized somatic variant scoring with Explainable Machine Learning models leading to better somatic filtering throughout the sensitivity scale. 3) Integration with Sequence Tube Map for enhanced visualization of variants with aligned sample reads in graph space. When benchmarked against enhanced two-tech truth sets generated using high-coverage short-read (Illumina) and long-read (Oxford Nanopore) data from four well characterized matched tumor/normal cell lines, Lancet2 outperformed other industry-leading tools in variant calling performance, especially for InDels. In addition, significant runtime performance improvements compared to Lancet1 ([~]10x speedup and 50% less peak memory usage) and most other state of the art somatic variant callers (at least 2x speedup with 8 cores or more) make Lancet2 an ideal tool for accurate and efficient somatic variant calling.

bioinformatics↗

bioRxiv2022

Childhood cancer mutagenesis caused by a domesticated DNA transposase

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer. One-Sentence SummaryInduction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.

cancer biology↗