Biology subjects

Batty, P.

Publications and source records attributed to Batty, P..

6 recordsLinked to original sources

bioRxiv2026

Induced Estrogen Receptor SUMOylation drives SERD activity

The ligand dependent transcription factor estrogen receptor (ER) is a key driver of and important drug target in breast cancer. Patients with advanced disease are typically treated with selective ER degraders (SERDs), whose therapeutic activity is commonly attributed to induced ER protein degradation. Yet the exact mechanism and relevance of degradation for clinical efficacy remain unclear. We show that SERDs directly induce ER SUMOylation, thereby triggering degradation via SUMO-targeted ubiquitin ligases (STUbLs). Inactivation of STUbLs prevents ER degradation and counterintuitively further sensitizes breast cancer cells to SERDs, rather than conferring resistance. SERD efficacy is independent of ER degradation, challenging the degradation-centric model of SERD action. Instead, SUMOylation recruits transcriptional co-repressors, turning SUMOylated ER into a dominant-negative repressor. Thus, SUMOylation rather than degradation is the direct consequence and driver of SERD activity. Our findings position SUMO-inducing drugs as a hitherto underappreciated yet clinically validated therapeutic modality with broad applicability.

Cancer Biology↗

bioRxiv2025

Leukemia Risk Factor ARID5B Coordinates HDAC-Mediated Transcriptional Repression

Multiple genetic association studies linked variants at ARID5B with predisposition to B-cell derived acute lymphoblastic leukemia (B-ALL) in children. Still, the molecular function of ARID5B remains largely uncharacterized. Here, we employ a combination of proteomics, genomics and transcriptomics to describe the molecular mechanisms of ARID5B. We identify that ARID5B interacts with MIER1, C16ORF87, HDAC1 and HDAC2 forming a chromatin repressor complex. By CUT&RUN, we mapped ARID5B binding in active regions of the genome, tethering HDAC1 and HDAC2 to distal regulatory elements and promoters. Genes actively repressed by the ARID5B repressor complex are involved in B cell proliferation and B cell-specific signaling. Together, we describe how ARID5B assembles into a repressor complex and regulates B cell-specific processes. Understanding its molecular mechanism will help elucidating how non-coding germline variants at ARID5B predispose to B-ALL.

cancer biology↗

bioRxiv2025

Disruption of the SAGA CORE triggers collateral degradation of KAT2A

The SAGA transcriptional co-activator complex regulates gene expression through histone acetylation at promoters, mediated by its histone acetyl transferase, KAT2A. While its structure and function have been extensively investigated, how the stability of individual subunits of SAGA, including KAT2A, is regulated, remains unclear. Here, using a fluorescence-based KAT2A stability reporter, we systematically dissect the molecular dependencies controlling KAT2A protein abundance. We identify the non-enzymatic SAGA CORE module subunits--TADA1, TAF5L, and TAF6L-- as necessary for KAT2A stability, with loss of these subunits disrupting the integrity of SAGA, leading to non-chromatin-bound KAT2A that is degraded by the proteasome, consequently leading to reduced H3K9 acetylation. Proteomic profiling reveals progressive loss of CORE and HAT components upon acute disruption of the SAGA CORE, indicating that an intact CORE is required for the stability of numerous components of SAGA. Finally, a focused CRISPR screen of ubiquitin-proteasome system genes identifies the E3 ligase UBR5, a known regulator of orphan protein degradation, and the deubiquitinase OTUD5, as regulators of KAT2A degradation when the SAGA CORE is perturbed. Together, these findings reveal a dependency of KAT2A protein stability on SAGA CORE integrity and define an orphan quality control mechanism targeting unassembled KAT2A, revealing a potential vulnerability in SAGA-driven malignancies.

molecular biology↗

bioRxiv2025

Conformational asymmetry of replicated human chromosomes

DNA replication creates two sister chromatids that must acquire specific three-dimensional conformations to support genome function and stability. This organization is largely mediated by cohesin complexes, which extrude intra-chromosomal loops and link two chromatids, thus forming "chromatid cohesion". Although sister chromatids are genetically identical, the replication process is intrinsically asymmetric: each chromatid inherits a different parental DNA strand, while the new strands are synthesized using distinct "leading" and "lagging" mechanisms of the replication fork. Whether and how this molecular asymmetry impacts higher-order chromatin organization remains unknown. Using sister-chromatid-sensitive Hi-C, strand-specific FISH, and polymer modeling, we reveal a consistent, genome-wide shift in sister chromatid alignment, biased along the 5'-3' direction of the inherited strands. This shift persists without loop extrusion but is lost upon disruption of cohesion, implicating cohesive cohesins in maintaining the displacement. Polymer simulations indicate that a modest ([~]100 kb) misalignment of "cohesive" cohesins is responsible for the observed asymmetry. We propose two mechanistic models that explain how this displacement arises from replication fork asymmetry: either through the dislocation of cohesin during replication or through the asymmetric anchoring and subsequent random sliding of cohesin pairs. These findings reveal a previously unrecognized chromosome-scale asymmetry in sister chromatid organization, which has implications for homology search during DNA repair.

molecular biology↗

bioRxiv2023

Cohesin-mediated DNA loop extrusion resolves sister chromatids in G2 phase

Genetic information is stored in linear DNA molecules, which fold extensively inside cells. DNA replication along the folded template path yields two sister chromatids that initially occupy the same nuclear region in a highly intertwined arrangement. Dividing cells must disentangle and condense the sister chromatids into separate bodies such that a microtubule-based spindle can move them to opposite poles. While the spindle-mediated transport of sister chromatids has been studied in detail, the chromosome-intrinsic mechanics pre-segregating sister chromatids have remained elusive. Here, we show that human sister chromatids resolve extensively already during interphase, in a process dependent on the loop-extruding activity of cohesin, but not that of condensins. Increasing cohesins looping capability increases sister DNA resolution in interphase nuclei to an extent normally seen only during mitosis, despite the presence of abundant arm cohesion. That cohesin can resolve sister chromatids so extensively in the absence of mitosis-specific activities indicates that DNA loop extrusion is a generic mechanism for segregating replicated genomes, shared across different Structural Maintenance of Chromosomes (SMC) protein complexes in all kingdoms of life.

cell biology↗

bioRxiv2022

Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms

Cohesin connects CTCF binding sites and other genomic loci in cis to form chromatin loops, and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here we describe a cohesin hinge mutant, which can extrude DNA into loops but is unable to mediate cohesion. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesins cohesion and loop extrusion activities can be separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wildtype cohesin. This suggests that cohesion establishment and cohesins interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.

cell biology↗