Biology subjects

Karam, E.

Publications and source records attributed to Karam, E..

3 recordsLinked to original sources

bioRxiv2025

Fission yeast histone chaperone Rtt106 regulates histone levels, prevents early division, and promotes genome stability

Chromatin packaging influences gene expression and is linked to genome stability through the establishment and maintenance of histone modifications. Histone chaperone proteins regulate chromatin assembly and thus packaging. We tested how loss of the histone chaperone Rtt106 affects genome stability through cell cycle checkpoint stability in response to cellular stress. We tested how double mutants lacking DNA replication or DNA damage checkpoint kinases are impacted by the absence of histone chaperone rtt106. Rtt106 brings histone H3 and histone H4 together into complexes. We found that rtt106{Delta} cells with loss of the DNA replication checkpoint (cds1{Delta}, rad3{Delta}) were more sensitive to hydroxyurea. However, DNA damage kinase chk1{Delta} rtt106{Delta} cells became less sensitive to DNA damaging drugs. The effects of Rtt106 on growth are observed in division timing, where rtt106{Delta} cells show early division in the presence of drug. Coupled to a decrease in histone H3 levels and increased mutation rate, our work shows how non-essential Rtt106 activities contribute to genome stability. By regulating histone levels and use, Rtt106 regulates the cell division and may function in chromatin arm coherence and segregation.

genetics↗

bioRxiv2025

Checkpoint-dependent sensitivities to nucleoside analogues uncover specific patterns of genomic instability

Nucleoside analogues are used as drugs and as labels in lab-based research. However, the effect of different nucleoside analogue mechanism(s) on cell sensitivity or mutagenesis is unclear. This is particularly important in cancer treatments where checkpoint proteins and DNA damage factors are often mutated. We tested 6 nucleoside analogues in the fission yeast, Schizosaccharomyces pombe. We found that the mutations in the DNA replication checkpoint cause unique sensitivity profiles towards chemotherapeutic nucleoside analogues (gemcitabine, 5-fluorouracil, cytarabine) and the non-clinical analogue bromodeoxyuridine. Antiretroviral compounds, zidovudine and lamivudine, did not alter cell growth. We compared half-maximal inhibitory concentration (IC50) doses between checkpoint deficient yeast strains, examining culture growth and DNA mis-segregation. Intriguingly, gemcitabine and bromodeoxyuridine doses above the IC50 promoted better growth. Above each compounds IC50 dose we saw that cells were insensitive to nucleoside analogue re-exposure, particularly in DNA replication checkpoint mutants (cds1{Delta}, rad3{Delta}). Thus, pairing nucleoside analogue use with personal genomics may inform drug choice, dose, and schedule. Finally, these data indicate that resistance may be predictable, informing clinical strategy.

cell biology↗

bioRxiv2024

D2-expressing neurons of the anterior paraventricular nucleus of the thalamus modulate learned aversive and safety salience

Associative learning provides a means to assign appropriate value signals to experiences that animals can later use to make appropriate value-based choices. By generalizing from prior aversive experiences and comparing with a current experience, animals can learn the relative aversive ("better or worse than") value or relative positive safety value between experiences. Yet, how such relative value signals are acquired during learning remain poorly known. The paraventricular nucleus of the thalamus (PVT) is critical for the control of salience and valence signals. It is therefore well-placed to be involved in learning relative aversive value and learned safety. Using a newly-developed conditioned place preference task, we uncover specific behavioral signatures associated with learning relative aversive value and learned safety, and related value-based choices. We then show that neurons expressing dopamine D2 receptor (D2+) in the anterior PVT (aPVT) are preferentially recruited by both relative aversive value learning and learned safety. Using a pharmacogenetic strategy, we demonstrate that aPVT D2+, but not D2-, neurons are involved in learning relative- but not absolute- aversive value. Finally, we show that aPVT D2+, but not D2-, neurons are also critical for the encoding of learned safety. Overall, our findings reveal a novel role of aPVT D2+ neurons in computing relative aversive/safety value signals between experiences during learning to promote appropriate value-based choices.

animal behavior and cognition↗