The Novel Role of Cell Cycle Checkpoint Clamp Rad9-Hus1-Rad1 (the 9-1-1 complex) in DNA repair pp. 41-74
Authors: (Amrita Madabushi and A-Lien Lu)
Abstract: Genotoxic stress damages DNA and exerts deleterious effect on cells resulting in genetic instability. DNA repair pathways are critical components of the cellular defense against cancer and aging. Eukaryotes have evolved complex regulatory mechanisms that coordinate DNA repair with DNA replication, cell cycle regulation, and transcription. Following DNA damage, the cell cycle checkpoints induce signal transduction cascades which arrest cell cycle progression, enhance DNA repair, and can stimulate apoptosis. The heterotrimeric sliding clamp Rad9-Rad1-Hus1 (the 9-1-1 complex) acts as a cell cycle checkpoint sensor and is loaded onto DNA by Rad17-RFC clap loader. Besides serving as damage sensor, recent findings indicate that the 9-1-1 complex is a component of base excision (BER), mismatch repair (MMR), and nucleotide excision repair (NER) pathways. The 9-1-1 complex interacts with and stimulates several DNA glycosylases, the first enzyme of the BER cascade, including MutY homolog (MYH), 8-oxoG glycosylase (OGG1), Nei-like protein (NEIL1), thymineDNA glycosylase (TDG), and methyl-binding domain IV (MBD4).MYH, OGG1, and NEIL1 are involved in the repair of oxidized bases while TDG and MBD4 are responsible for removing thymine and uracil in T/G and U/G mispairs arisen through deamination. The 9-1-1 complex also interacts with and stimulates other components of BER including DNA polymerase (POLβ), apurinic/apyrimidinic endonuclease 1 (APE1), flap endonuclease 1 (FEN1), replication protein A (RPA), and DNA ligase l (LIG1). Thus, the 9-1-1 complex serves as a BER component and may provide a platform to coordinate the BER process.
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