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Department of Biophysics, Graduate School of Science, Kyoto
University, Kitashirakawa-Oiwake, Sakyo-ku, Kyoto, 606, Japan
Fission yeast Cut5/Rad4 plays a unique role in the
genome maintenance as it is required for replication, replication
checkpoint, and normal UV sensitivity. It is unknown, however, how Cut5
protein is linked to other checkpoint proteins, and what part it plays in replication and UV sensitivity. Here we report that Cut5 interacts with a novel checkpoint protein Crb2 and that this interaction is
needed for normal genome maintenance. The carboxyl terminus of Crb2
resembles yeast Rad9 and human 53BP1 and BRCA1. Crb2 is required for
checkpoint arrests induced by irradiation and polymerase mutations, but
not for those induced by inhibited nucleotide supply. Upon UV damage,
Crb2 is transiently modified, probably phosphorylated, with a similar
timing of phosphorylation in Chk1 kinase, which is reported to restrain
Cdc2 activation. Crb2 modification requires other damage-sensing
checkpoint proteins but not Chk1, suggesting that Crb2 acts at the
upstream of Chk1. The modified Crb2 exists as a slowly sedimenting
form, whereas Crb2 in undamaged cells is in a rapidly sedimenting
structure. Cut5 and Crb2 interact with Chk1 in a two-hybrid system.
Moreover, moderate overexpression of Chk1 suppresses the phenotypes of
cut5 and crb2 mutants. Cut5, Crb2, and Chk1 thus may
form a checkpoint sensor-transmitter pathway to arrest the cell cycle.
[Key Words: UV damage; hydroxyurea; DNA polymerase; phosphorylation; two-hybrid screen]
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