Study 1 - Histones play a critical role in regulating chromatin structure and function within nucleosomes. They participate in DNA transcription, repair, and replication. We present a rapid, efficient, and versatile method for isolating nucleosomal histones from mammalian cells and tissues, eliminating the need for acidic or high-salt conditions commonly used in other isolation techniques. Our protocol employs readily available and affordable laboratory chemicals and simple equipment. Evaluation of the protocol on six cell lines and two animal tissue samples demonstrated that the gentle extraction conditions preserved the delicate epigenetic changes in histones, allowing for downstream analyses of histone variants and posttranslational modifications. We have demonstrated that our procedure is effective for identifying alterations in the transcriptional activity of histone genes in various stages of the cell cycle, and as a consequence of DNA damage. The isolated histone fractions can be utilized for various applications, including electrophoresis, immunoblotting, and mass spectrometry. Therefore, our proposed method for nucleosomal histone isolation is sensitive, specific, and suitable for diverse downstream applications. Study 2 - The development of hepatocellular carcinoma (HCC) involves numerous cellular processes, among which is endoplasmic reticulum (ER) stress. ER stress occurs due to a build-up of incorrectly folded or unfolded proteins, leading to the activation of the unfolded protein response (UPR) pathway which aims to re-establish ER homeostasis. Currently, a biallelic mutation in the SPRTN gene is the sole recognized single-gene mutation associated with early-onset HCC. The mechanism by which SPRTN mutations lead to HCC is unclear. The SPRTN protein participates in the repair of DNA damage from DNA-protein crosslinks (DPC). To our knowledge, SPRTN's role in the ER stress response has not yet been investigated. Our study focused on the involvement of SPRTN in the ER stress response and its significance in the progression of HCC. We detected alterations in SPRTN and UPRrelated genes and proteins in HCC samples. We found that SPRTN interacts with the UPR sensor GRP78. SPRTN-depleated cells are more susceptible to ER stress and UPR-induced DNA damage, emphasizing SPRTN's vital role in managing ER stress. This novel function of SPRTN protease could help elucidate mechanisms of HCC development.