The H2A N-terminal tail is required to alleviate copper-induced stress in Saccharomyces cerevisiae.

Histone tail residues drive many biological processes by regulating genome-wide transcription. Functions of histone H3 and H4 tail residues in stress-responsive gene transcriptional programs have been extensively studied. The H2A tail residues have been shown to regulate DNA damage repair and oxidative stress response, but the involvement of N-terminal tail of H2A (H2ANtT) in proteostasis regulation is unknown. The unfolded protein response pathway (UPR) is an essential mechanism adopted by cells to prevent protein toxicity in response to ER stress. The disturbance in ER can occur by various factors such as heat stress, redox imbalance, exposure to xenobiotics and metals. Copper is utilized as a cofactor by cellular enzymes, but excessive copper affects ER homeostasis. We found that cells lacking 1-20 residues of H2ANtT are intolerant to copper stress, owing to the accumulation of misfolded proteins in the mutant cells. H2A 1-20 truncation also reduces the physiological UPR, and copper exposure further aggravates this effect. Furthermore, the expression of a spliced version of HAC1 mRNA in H2A∆(1-20) cells, encoding the downstream transcription factor of UPR signalling, rescues their growth under copper stress. Altogether these results provide evidence that H2ANtT reduces copper-induced ER stress by regulating UPR signalling.