not The third component of the yeast adaptation response to HMF involves degradation of damaged proteins and protein modifications mainly regulated by transcription factor genes RPN4 and HSF1. Chemical stress causes damage to protein conformation leading to protein unfolding and aggregation. Small heat shock pro teins, acting as chaperones, assist in folding or refolding nascent or denatured proteins and enzymes to maintain a functional conformation. In this study, we found HSP26 and SSA4 encoding chaperones were significantly induced to counteract HMF stress damage to proteins. The deletion mutation of SSA4 displayed a significant longer lag phase under the HMF challenge, indicating its important role in adaptation and tolerance to HMF.

While the presence of chaperones provides positive con tribution to protein protection, severe or prolonged stress condition can result in irreversible protein damage. Misfolded or damaged proteins, especially aggregated proteins are highly toxic to cells. Degra dation of misfolded and damaged proteins by the ubi quitin mediated proteasome pathway plays an important genes of multiple functional categories are associated with the yeast adaptation to the inhibitor HMF during the lag phase. Transcription factor genes YAP1, PDR1, PDR3, RPN4, and HSF1 were identified as key regulatory genes for yeast global adaptation. Functional enzyme coding genes, for example ARI1, ADH6, ADH7, and OYE3, as well as gene interactions involved in the bio transformation and regulated by YAP1, are directly involved in the conversion of HMF into the less toxic compound FDM.

PDR genes encode plasma membrane proteins and function as transporter of ATP binding cassette proteins. The large number of induced PDR genes observed by our study suggests a hypothesis of the important PDR function of pumping HMF and endogenous toxic Brefeldin_A metabolites to maintain cell viability. Important PDR gene functions include specific transpor ter ATPase gene RSB1, toxin transporter genes TPO1 and TPO4, and multiple cellular transport facilitator role in maintaining normal cell function and viability. Denatured proteins are targeted via the cova lent attachment of ubiquitin to a lysine side chain, and polyubiquitinated proteins are finally delivered to protea some to be degraded. We observed that at least 14 ubi quitin related and proteasome genes were induced by HMF, indicating their important functions in adaptation to the HMF stress.

Strains with deletion mutations in these genes were sensitive to HMF with an extended lag phase, for example, genes OTU1 and SHP1. It was suggested that the degradation of pro teins by the ubiquitin mediated proteasome pathway has regulatory roles on cell cycle, metabolic adaptations, gene regulation, development, and differentiation.

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