Biology subjects

Geri, J.

Publications and source records attributed to Geri, J..

3 recordsLinked to original sources

bioRxiv2026

AR-V7 Utilizes a Noncanonical Nuclear Localization Signal to Sustain Androgen-Independent Nuclear Import and Signaling

AR-V7 is the most prevalent androgen receptor splice variant in metastatic castration-resistant prostate cancer, yet how it enters the nucleus independently of androgen binding has remained unclear. We previously demonstrated that AR-V7 undergoes nuclear import via a non-canonical pathway distinct from the microtubule-based, importin-/{beta}- and Ran-dependent mechanism used by full-length AR. Here, using systematic truncation and alanine-scanning mutagenesis, we identify a non-classical nuclear localization motif at the junction of the DNA-binding domain (DBD) and cryptic exon 3 (CE3) that is required for efficient AR-V7 nuclear import. Specific basic residues within the DBD and CE3 are required not only for nuclear entry but also for transcriptional activity. Unexpectedly, mutants retaining partial nuclear localization were transcriptionally silent, suggesting that CE3 contributes to transcriptional engagement through mechanisms separate from nuclear transport. Genome-wide transcriptomic analysis of a strongly import-deficient mutant confirmed that disruption of nuclear entry abolishes the AR-V7 transcriptional program. To map compartment-specific protein interactions, we applied antibody-guided photocatalytic proximity labeling. Nuclear AR-V7 associated most prominently with both canonical BAF and PBAF SWI/SNF chromatin remodeling complexes, together with known transcriptional coregulators and DNA-repair factors, whereas the cytoplasm-restricted mutant engaged different networks centered on mRNA deadenylation and decay, cytoskeletal regulation, and chaperone systems. Together, these findings define a variant-specific NLS, separate nuclear import from CE3-dependent transcriptional competence, and identify the cytoplasmic networks that become accessible when AR-V7 nuclear entry is impaired. They reveal two mechanistically distinct vulnerabilities for suppressing AR-V7 signaling: blocking nuclear translocation and disrupting CE3-dependent transcriptional engagement within the nucleus.

cancer biology↗

bioRxiv2025

NAD⁺ Replenishment Mitigates Cardiomyocyte Senescence and Corrects Heart Failure with Preserved Ejection Fraction in Aged Mice

Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD levels, impaired NAD biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD depletion promoted senescence, which was reversed by the NAD precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD availability as a critical regulator of cardiac senescence and support NAD precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.

pharmacology and toxicology↗

bioRxiv2023

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance behavior when circulating estrogen was high during the proestrus phase of the estrous cycle than when it was low, contributing to sex differences in these behaviors. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen state occurred via rapid estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking behavior. This study is the first to demonstrate a rapid, nongenomic signaling mechanism for ovarian-derived estrogen signaling in the brain controlling behavior in gonadally intact females, and it establishes a causal role for estrogen in an intact hormonal context for driving alcohol consumption that contributes to known sex differences in this behavior.

neuroscience↗