Nagar S, Mehta R, Kaur P, Liliah RT, Vancura A

One of the key outcomes of activation of DNA replication checkpoint (DRC) or DNA damage checkpoint (DDC) is the increased synthesis of the deoxyribonucleoside triphosphates (dNTPs), which is a prerequisite for normal progression through the S phase and for effective DNA repair. We have recently shown that DDC increases aerobic ...

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metabolism and activates the electron transport chain (ETC) to elevate ATP production and dNTP synthesis by repressing transcription of histone genes, leading to globally altered chromatin architecture and increased transcription of genes encoding enzymes of tricarboxylic acid (TCA) cycle and the ETC. The aim of this study was to determine whether DRC activates ETC. We show here that DRC activates ETC by a checkpoint kinase Dun1p-dependent mechanism. DRC induces transcription of RNR1-4 genes and elevates mtDNA copy number. Inactivation of RRM3 or SGS1, two DNA helicases important for DNA replication, activates DRC but does not render cells dependent on ETC. However, fitness of rrm3? and sgs1? cells requires Dun1p. The slow growth of rrm3?dun1? and sgs1?dun1? cells can be suppressed by introducing sml1? mutation, indicating that the slow growth is due to low levels of dNTPs. Interestingly, inactivation of ETC in dun1? cells results in a synthetic growth defect that can be suppressed by sml1? mutation, suggesting that ETC is important for dNTP synthesis in the absence of Dun1p function. Together, our results reveal an unexpected connection between ETC, replication stress, and Dun1p kinase.

Date: Jan. 01, 2023

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