Abstract
The Saccharomyces cerevisiae Fun30 chromatin remodeler has recently been shown to facilitate long-range resection of DNA double strand break (DSB) ends, which proceeds homologous recombination (HR). This is believed to underlie the role of Fun30 in promoting cellular resistance to DSB inducing agent camptothecin. We show here that Fun30 also contributes to cellular resistance to genotoxins methyl methanesulfonate (MMS) and hydroxyurea (HU) that can stall the progression of DNA replication. We present evidence implicating DNA end resection in Fun30-dependent MMS-resistance. On the other hand, we show that Fun30 deletion suppresses the MMS- and HU-sensitivity of cells lacking the Rad5/Mms2/Ubc13-dependent error-free DNA damage tolerance mechanism. This suppression is not the result of a reduction in DNA end resection, and is dependent on the key HR component Rad51. We further show that Fun30 negatively regulates the recovery of rad5Δ mutant from MMS induced G2/M arrest. Therefore, Fun30 has two functions in DNA damage repair: one is the promotion of cellular resistance to genotoxic stress by aiding in DNA end resection, and the other is the negative regulation of a Rad51-dependent, DNA end resection-independent mechanism for countering replicative stress. The latter becomes manifest when Rad5 dependent DNA damage tolerance is impaired. In addition, we find that the putative ubiquitin-binding CUE domain of Fun30 serves to restrict the ability of Fun30 to hinder MMS- and HU-tolerance in the absence of Rad5.
Highlights
Genotoxic agents may cause DNA damage and/or block DNA replication leading to genome instability, and cells have evolved a variety of mechanisms to counter the effects of these agents on DNA
DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR) or non-homologous end joining (NHEJ), and single-strand DNA damages are subject to repair by nucleotide excision repair (NER), base excision repair (BER), or DNA mismatch repair (MMR) [2,3,4,5,6]
It has been shown that Fun30 is recruited to DSBs and facilitates the resection of DSB ends, which is believed to aid in subsequent HR repair [23,24,25]
Summary
Genotoxic agents may cause DNA damage and/or block DNA replication leading to genome instability, and cells have evolved a variety of mechanisms to counter the effects of these agents on DNA. These mechanisms include DNA damage repair and tolerance/bypass pathways as well as DNA damage checkpoints [1]. DNA damage tolerance (DDT) ( know as DNA damage bypass, DDB, and post-replication repair, PRR) pathways enable DNA replication to pass through the damaged bases without repairing them, thereby allowing the completion of DNA replication, and leaving the damages to be repaired after DNA replication [7,8]
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