Biology subjects

Foster, B. M.

Publications and source records attributed to Foster, B. M..

3 recordsLinked to original sources

bioRxiv2025

UFMylation orchestrates chromatin engagement of core NHEJ components to promote DNA double-strand break repair

DNA double-strand breaks (DSBs) are highly cytotoxic lesions whose misrepair can lead to genomic instability, cancer and developmental disorders. Through systematic screening of understudied ubiquitin-like modifiers (UBLs), we identify UFM1 as a previously unrecognised regulator of non-homologous end-joining (NHEJ). Using a structure-guided chemical biology strategy, we develop a photo-crosslinkable UFM1 probe and, together with high-resolution NMR, uncover non-canonical UFM1-binding regions in core NHEJ components, including XRCC4. Mechanistically, proximity-dependent proteomics reveals Ku70 as a key UFMylation substrate, establishing a functional axis in which XRCC4 engages UFMylated Ku70 to promote the chromatin assembly of NHEJ factors. Perturbation of UFM1 signalling, via UFSP2 depletion or a hypomorphic UBA5 allele in patient-derived fibroblasts, impairs these processes, linking UFMylation defects to altered regulation of DSB repair. Our findings define a complete UFM1 signalling module in genome maintenance and uncover a molecular connection between hereditary UFMylation disorders and dysregulated DSB repair pathways.

molecular biology↗

bioRxiv2021

Knockout of a single Sox gene resurrects an ancestral cell type in the sea anemone Nematostella vectensis

Cnidocytes are the explosive stinging cells found only in cnidarians (corals, jellyfish, etc). Specialized for prey capture and defense, cnidocytes are morphologically complex and vary widely in form and function across taxa; how such diversity evolved is unknown. Using CRISPR/Cas9-mediated genome editing in the burrowing sea anemone Nematostella vectensis, we show that a single transcription factor (NvSox2) acts as a binary switch between two alternative cnidocyte fates. Knockout of NvSox2 caused a complete transformation of nematocytes (piercing cells) into spirocytes (ensnaring cells). The type of spirocyte induced by NvSox2 knockout (robust spirocyte) is not normally found in N. vectensis but is common in sea anemones from other habitats. Homeotic control of cell fate provides a mechanistic explanation for the discontinuous distribution of cnidocyte types across cnidarians and demonstrates how simple counts of cell types can underestimate biodiversity.

evolutionary biology↗

bioRxiv2018

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

Metastasis is the primary cause of cancer patient morbidity and mortality but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patients' tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. In our analyses, CD117 was expressed in several tissues and was highly expressed in bone marrow progenitor cells. Also, we uncovered that CD117 gene amplifications and mutations occurred in multiple cancers. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. These signaling pathways were commonly altered in patients with CD117 amplifications and mutations. Here, we examine evidence that the SCF/CD117 signaling axis controls cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.\n\nAbbreviations

cancer biology↗