砷暴露与许多癌症的风险增加相关，而表观遗传机制在砷介导的致癌过程中起着关键作用。我们先前的研究表明，砷暴露引发了H3.1 mRNA的多腺苷酸化，并抑制了H3.3在关键基因调控元件上的沉积。然而，相关的确切机制尚不清楚。为了揭示H3.1 mRNA多腺苷酸化引发的砷诱导H3.3组装抑制的调控因子，我们使用质谱法鉴定了在砷暴露和H3.1 mRNA多腺苷酸化过表达条件下与H3.3结合亲和力降低的蛋白质，尤其是组蛋白伴侣。我们的研究结果揭示，H3.3和组蛋白伴侣蛋白MCM2之间的相互作用在人类肺上皮细胞BEAS-2B中通过H3.1 mRNA多腺苷酸化过表达和砷处理均减弱。由于H3.1蛋白水平的升高，MCM2与H3.1的结合增加，从而减少了MCM2可用于H3.3的含量。为了进一步研究MCM2在砷暴露和H3.1 mRNA多腺苷酸化过程中的作用，我们在过表达H3.1多腺苷酸化或暴露于砷的BEAS-2B细胞中过表达MCM2。我们的结果表明，MCM2过表达减弱了多个基因组位点处H3.3的丧失，暗示其参与了由H3.1 mRNA多腺苷酸化介导的砷诱导的H3.3位点位移。这些发现表明，由于H3.1 mRNA多腺苷酸化的产生，组蛋白伴侣MCM2和H3.3之间的结合关系的改变可能在砷诱导的致癌过程中发挥关键作用。Copyright © 2023. Elsevier Inc.出版。

Arsenic exposure is associated with an increased risk of many cancers, and epigenetic mechanisms play a crucial role in arsenic-mediated carcinogenesis. Our previous studies have shown that arsenic exposure induces polyadenylation of H3.1 mRNA and inhibits the deposition of H3.3 at critical gene regulatory elements. However, the precise underling mechanisms are not yet understood. To characterize the factors governing arsenic-induced inhibition of H3.3 assembly through H3.1 mRNA polyadenylation, we utilized mass spectrometry to identify the proteins, especially histone chaperones, with reduced binding affinity to H3.3 under conditions of arsenic exposure and polyadenylated H3.1 mRNA overexpression. Our findings reveal that the interaction between H3.3 and the histone chaperon protein MCM2 is diminished by both polyadenylated H3.1 mRNA overexpression and arsenic treatment in human lung epithelial BEAS-2B cells. The increased binding of MCM2 to H3.1, resulting from elevated H3.1 protein levels, appears to contribute to the reduced availability of MCM2 for H3.3. To further investigate the role of MCM2 in H3.3 deposition during arsenic exposure and H3.1 mRNA polyadenylation, we overexpressed MCM2 in BEAS-2B cells overexpressing polyadenylated H3.1 or exposed to arsenic. Our results demonstrate that MCM2 overexpression attenuates H3.3 depletion at several genomic loci, suggesting its involvement in the arsenic-induced displacement of H3.3 mediated by H3.1 mRNA polyadenylation. These findings suggest that changes in the association between histone chaperone MCM2 and H3.3 due to polyadenylation of H3.1 mRNA may play a pivotal role in arsenic-induced carcinogenesis.Copyright © 2023. Published by Elsevier Inc.