A society that threatens scientists with legal repercussions for advising the government and authorities during the COVID pandemic, not only risks losing scientific expertise needed for the next crisis but also its science and its future.
Hearing relies on the lifelong stability of the actin core within hair cell stereocilia, yet the molecular mechanisms ensuring this stability are largely unknown. Here, we identify the transcription factor Sox3 as a key regulator of this core structure in mice. In the absence of Sox3, the stereocilia core progressively disassembles, leading to hearing loss and impaired mechanotransduction. Sox3-deficient stereocilia are also more susceptible to acoustic trauma and fail to repair structural gaps, whereas Sox3 overexpression confers resilience against noise-induced damage. Mechanistically, Sox3 deletion downregulates β-thymosin genes in hair cells, most prominently Tmsb10, an essential regulator of actin monomer availability. Depleting Tmsb10 recapitulates the core degeneration observed in Sox3-deficient hair cells, establishing the Sox3-Tmsb10 axis as a novel molecular mechanism governing the lifelong preservation of the stereocilia actin core. This regulatory pathway also represents a promising target for therapeutic intervention in noise-induced hearing loss. Sox3 ablation progressively disrupts the stereocilia actin core, impairing MET function and increasing susceptibility to acoustic trauma while targeted Sox3 overexpression protects against noise-induced damage. Sox3 ablation progressively disrupts the stereocilia actin core, impairing MET function and increasing susceptibility to acoustic trauma while targeted Sox3 overexpression protects against noise-induced damage.
Axon initiation is a critical step in the establishment of neuronal morphology. However, the mechanisms regulating stable axon initiation during embryonic development remain poorly understood. Here, using fixed-tissue super-resolution and high-resolution live-tissue imaging in the developing chick spinal cord, we reveal that stable axon initiation is characterised by microtubule-directed neurofilament accumulation in the emerging axon, and identify the multifunctional G-protein Gαi2 as a regulator of this process. Before axon initiation, microtubule network orientation shifts towards the site of the future axon where coiled Gαi2-associated neurofilaments accumulate asymmetrically before unfurling into the initiating axon behind microtubules. Crucially, Gαi2 is associated with neurofilaments and microtubules at their points of contact. Gαi2 depletion reduces engagement between these cytoskeletal networks and leads to impaired passage of neurofilaments into initiating axons and disrupted axon outgrowth, supporting a role for Gαi2 in regulating microtubule-driven incorporation of neurofilaments in nascent axons. These findings advance mechanistic understanding of polarity establishment and provide insight into cytoskeletal regulation during axon formation. Live and super-resolution imaging of the developing chick spinal cord identifies a non-canonical role for Gαi2 in coupling neurofilament and microtubule networks, enabling microtubule-driven neurofilament incorporation into nascent axons that promotes persistent axon outgrowth. Live and super-resolution imaging of the developing chick spinal cord identifies a non-canonical role for Gαi2 in coupling neurofilament and microtubule networks, enabling microtubule-driven neurofilament incorporation into nascent axons that promotes persistent axon outgrowth.
Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers. However, their durable benefit is severely limited by resistance and hematologic toxicity. PARPi are also largely ineffective in homologous recombination-proficient tumors, especially CCNE1-amplified cancers, which remain therapeutically intractable. We show that loss of the chromatin remodeler Amplified in Liver Cancer 1 (ALC1) markedly sensitizes serous ovarian cancer cells, xenografts, and patient-derived models to PARPi across both HRD and CCNE1-amplified contexts. Unlike other PARPi sensitizers, ALC1 depletion circumvents clinically relevant PARPi resistance while sparing BRCA wild-type and heterozygous nonmalignant cells, revealing an unusually wide therapeutic index. Mechanistically, this selectivity is dictated by intrinsic replication-stress burden, which renders cancer cells uniquely dependent on ALC1-mediated stress tolerance. Accordingly, collective data from cell line and patient samples reveal endogenous phospho-T21 RPA2 as a predictive biomarker of PARPi responsiveness following ALC1 targeting. These findings establish ALC1 targeting as a mechanistically grounded, biomarker-guided strategy to safely expand PARPi efficacy and support the clinical advancement of ALC1 inhibitors currently in Phase I trials. ALC1 targeting safely broadens the therapeutic index of PARP inhibitors in BRCA-mutant and CCNE1-amplified tumors. The replication stress marker pT21-RPA2 provides a clinically actionable biomarker to identify tumors most likely to respond to this approach. ALC1 targeting safely broadens the therapeutic index of PARP inhibitors in BRCA-mutant and CCNE1-amplified tumors. The replication stress marker pT21-RPA2 provides a clinically actionable biomarker to identify tumors most likely to respond to this approach.
DNA–RNA hybrids cause genome instability by promoting transcription-replication conflicts. However, as they are stimulated at double-stranded breaks (DSBs), they can also impact DSB repair. We investigated whether the RNA chaperon ALYREF and its RNA helicase partner UAP56/DDX39B, both of which regulate RNA biogenesis and R-loops, also act at DSBs. We found that ALYREF, but not UAP56/DDX39B, is recruited to DSBs. Recruitment is partially dependent on transcription and hybrids, and fully dependent on polyADP-ribose (PAR). Consistently, we show that ALYREF, but not UAP56/DDX39B, binds PAR in vitro. Notably, ALYREF overexpression delays DSB repair by retaining PAR levels and interfering with the loading dynamics of early DSB repair factors that regulate DNA resection. Interestingly, we detect high ALYREF levels in numerous cancer subtypes by database analysis. We propose that ALYREF, when overexpressed, induces genome instability in tumoral cells by interfering with DSB repair. The RNA chaperon ALYREF binds to damaged DNA via polyADP-ribose and its overexpression delays DNA repair. ALYREF is highly expressed in many tumors, suggesting that it can act as a tumor driver by impairing DNA repair. The RNA chaperon ALYREF binds to damaged DNA via polyADP-ribose and its overexpression delays DNA repair. ALYREF is highly expressed in many tumors, suggesting that it can act as a tumor driver by impairing DNA repair.
