ReviewDial 9–1–1 for DNA damage: the Rad9–Hus1–Rad1 (9–1–1) clamp complex
Introduction
To ensure the stability of their genomes, cells activate complex signaling networks in response to DNA damage and replication stress [1], [2]. These pathways, termed checkpoint signaling pathways, first detect the damage and then transduce the signal to downstream effectors that block cell cycle progression, activate apoptosis, and influence DNA repair. The Rad9, Hus1, and Rad1 (using Schizosaccharomyces pombe nomenclature) orthologs, which form the Rad9–Hus1–Rad1 (9–1–1) complex, are conserved participants in checkpoint activation that play critical roles in cellular responses to DNA damage. For clarity, this review will use the S. pombe nomenclature to identify proteins in vertebrate systems. To refer to the Saccharomyces cerevisiae orthologs, we will use the S. pombe name followed by the S. cerevisiae name in parentheses (e.g., Rad9 (scDdcl)).
Section snippets
Biochemical function of the Rad9–Hus1–Rad1 (9–1–1) complex
The Rad9, Hus1, and Rad1 orthologs were initially found in genetic screens designed to identify genes that affected sensitivity to genotoxins. Although required for activation of checkpoint signaling pathways, the initial cloning of these genes did not provide clues to the functions of the encoded proteins, and it was not immediately obvious how they participated in checkpoint activation. Insight into the roles of these proteins came from studies using molecular modeling techniques, which
9–1–1’s role in checkpoint activation
The 9–1–1 complex is loaded onto chromatin in response to many different genotoxic stresses, including alkylation, ultraviolet light and ionizing radiation, and replication inhibitors, suggesting that the complex plays a role in the cellular responses activated by many types of DNA damage. Broadly speaking, these types of DNA damage activate two checkpoint signaling pathways, which regulate genotoxin-induced G1 arrest, S-phase slowing, G2/M arrest, apoptosis, and influence DNA repair. For
The role of the 9–1–1 complex in DNA repair
The role of the 9–1–1 complex in DNA repair has not been evaluated in mammalian cells; nonetheless, the heterotrimeric clamp’s role in DNA repair in yeast is now coming into focus. Thus, this review will examine the role of the 9–1–1 complex in DNA repair in yeast.
Summary
The identification of the biochemical function of the 9–1–1 subunits and their roles in checkpoint activation has proceeded at a rapid pace. These studies have given rise to a model in which genotoxins create DNA structures that lead to the loading of the 9–1–1 complex via the Rad17–RFC clamp-loading complex. Once bound to DNA, the 9–1–1 complex serves as a sliding clamp that functions as a central regulator of checkpoint activation and DNA repair by tethering specific proteins to the sites of
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