Abstract
DNA double-strand breaks (DSBs) are highly cytotoxic lesions that must be repaired to ensure genomic stability and avoid cell death. The cellular response to DSBs is initiated by the evolutionarily conserved Mre11-Rad50-Xrs2/NBS1 (MRX/MRN) complex that has structural and catalytic functions. Furthermore, it is responsible for DSB signaling through the activation of the checkpoint kinase Tel1/ATM. Here, we review functions and regulation of the MRX/MRN complex in DSB processing in a chromatin context, as well as its interplay with Tel1/ATM.
Highlights
Chromosomal DNA double-strand breaks (DSBs) are potentially lethal DNA lesions that can form accidentally during DNA replication and transcription, or upon exposure to genotoxic agents, such as ionizing radiation or chemicals
In S and G2 phases of the cell cycle, when Sae2 is phosphorylated by cyclin-dependent kinase (CDK) and ATP hydrolysis by Rad50 is allowed, the presence of Ku at the DSB ends renders the 5′ DNA strand susceptible to endonucleolytic cleavage by MRX-Sae2 that directs the repair toward homologous recombination (HR) (Figure 2)
Mutations that decrease either MRX/Rad9 association to DSBs or Rad53/Tel1 signaling restores DNA damage resistance in Sae2-deficient cells (Bonetti et al, 2015; Chen et al, 2015; Ferrari et al, 2015; Gobbini et al, 2015; Puddu et al, 2015; Yu et al, 2018). These findings indicate that Sae2 has an Mre11 nuclease-independent function in resection that counteracts the inhibition that Rad9 and Rad53 exert on Exo1 and Dna2-Sgs1
Summary
Chromosomal DNA double-strand breaks (DSBs) are potentially lethal DNA lesions that can form accidentally during DNA replication and transcription, or upon exposure to genotoxic agents, such as ionizing radiation or chemicals. The Sae2 protein (CtIP in mammals) stimulates Mre11 endonuclease activity to cleave the 5′-terminated DNA strands at both DSB ends (Cannavo and Cejka, 2014;Reginato et al, 2017; Wang et al, 2017).
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