Biology subjects

Brenner, J. C.

Publications and source records attributed to Brenner, J. C..

3 recordsLinked to original sources

bioRxiv2026

Rac1 and CHK1 Converge on Abi-1 to Regulate DNA Repair Dependency and Treatment Response in Human Cancers

Radiation therapy (RT) resistance remains a major clinical challenge, yet biomarkers guiding precision radiosensitization are lacking. We previously demonstrated that Rac1 promotes RT resistance in glioblastoma (GBM) by inducing Abi-1-S323 dephosphorylation and enhancing non-homologous end joining (NHEJ). Here, we identify Abi-1-S323 as a key regulator of DNA repair states and a determinant of therapeutic efficacy in human cancers. Clinically, loss of Abi-1-S323 phosphorylation was associated with poor outcomes in patients with RT-treated GBM. Bioinformatic analyses revealed that non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) are among the cancers with frequent RAC1 amplification, suggesting that these tumor types may have increased Rac1-Abi-1 signaling activity. Loss of Abi-1-S323 phosphorylation also predicted poor outcomes in patients with RT-treated HNC. Consistent with these clinical observations, high Rac1 activity and low Abi-1-S323 phosphorylation were associated with enhanced DNA double-strand break repair and radioresistance in NSCLC and HNC models, whereas genetic or pharmacological inhibition of this signaling impaired DNA repair and radiosensitized tumors in vitro and in vivo. Mechanistically, we identified CHK1 as a kinase that phosphorylates Abi-1 at S323 and defines an alternative homologous recombination (HR)-dependent repair state. Tumors with high Rac1-Abi-1 signaling exhibited elevated NHEJ capacity and were selectively radiosensitized by Rac1 inhibition, whereas tumors with low Rac1-Abi-1 signaling displayed high CHK1 activity, preferentially relied on HR, and were selectively radiosensitized by CHK1 inhibition. These findings establish Abi-1-S323 as a biomarker defining therapeutically distinct DNA repair states and provide a framework for precision radiosensitization.

cancer biology↗

bioRxiv2024

Conformational plasticity of a BiP-GRP94 chaperone complex

Hsp70/Hsp90-chaperones and their regulatory co-chaperones are critical for maintaining protein homeostasis. GRP94, the sole Hsp90-chaperone in the secretory pathway of mammalian cells, is essential for the maturation of important secretory and transmembrane proteins. Without the requirement of co-chaperones, the Hsp70-protein BiP controls regulatory conformational changes of GRP94 - the structural basis of which has remained elusive. Here, we biochemically and structurally characterize the formation of a BiP-GRP94 chaperone complex and its transition to a conformation expected to support the loading of substrate proteins from BiP onto GRP94. BiP initially binds to the open GRP94 dimer via an interaction interface that is conserved among Hsp70/90 paralogs. Subsequently, binding of a second BiP protein stabilizes a semi-closed GRP94 dimer, thereby advancing the chaperone cycle. Our findings highlight a fundamental mechanism of direct Hsp70/90 cooperation, independent of co-chaperones.

biochemistry↗

bioRxiv2021

SearcHPV: a novel approach to identify and assemble human papillomavirus-host genomic integration events in cancer

BackgroundHuman papillomavirus (HPV) is a well-established driver of malignant transformation in a number of sites including head and neck, cervical, vulvar, anorectal and penile squamous cell carcinomas; however, the impact of HPV integration into the host human genome on this process remains largely unresolved. This is due to the technical challenge of identifying HPV integration sites, which includes limitations of existing informatics approaches to discover viral-host breakpoints from low read coverage sequencing data. MethodsTo overcome this limitation, we developed a new HPV detection pipeline called SearcHPV based on targeted capture technology and applied the algorithm to targeted capture data. We performed an integrated analysis of SearcHPV-defined breakpoints with genome-wide linked read sequencing to identify potential HPV-related structural variations. ResultsThrough analysis of HPV+ models, we show that SearcHPV detects HPV-host integration sites with a higher sensitivity and specificity than two other commonly used HPV detection callers. SearcHPV uncovered HPV integration sites adjacent to known cancer-related genes including TP63 and MYC, as well as near regions of large structural variation. We further validated the junction contig assembly feature of SearcHPV, which helped to accurately identify viral-host junction breakpoint sequences. We found that viral integration occurred through a variety of DNA repair mechanisms including non-homologous end joining, alternative end joining and microhomology mediated repair. ConclusionsIn summary, we show that SearcHPV is a new optimized tool for the accurate detection of HPV-human integration sites from targeted capture DNA sequencing data.

bioinformatics↗