Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeast.
F. Al-Khodairy,E. Fotou,Katherine S. Sheldrick,Dominic J. F. Griffiths,Alan R. Lehmann,Antony M. Carr +5 more
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TL;DR: A study of the radiation sensitivity of these mutants through the cell cycle suggests that this second response is associated with S phase and that the checkpoint rad mutants, in addition to an inability to arrest mitosis after radiation, are defective in an S phase radiation checkpoint.
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Abstract: To investigate the mechanisms that ensure the dependency relationships between cell cycle events and to investigate the checkpoints that prevent progression through the cell cycle after DNA damage, we have isolated mutants defective in the checkpoint and feedback control pathways. We report the isolation and characterization of 11 new loci that define distinct classes of mutants defective in one or more of the checkpoint and feedback control pathways. Two mutants, rad26.T12 and rad27.T15, were selected for molecular analysis. The null allele of the rad26 gene (rad26.d) shares the phenotype reported for the "checkpoint rad" mutants rad1, rad3, rad9, rad17, and hus1, which are defective in the radiation checkpoint and in the feedback controls that ensure the order of cell cycle events. The null allele of the rad27 gene (rad27.d) defines a new class of Schizosaccharomyces pombe mutant. The rad27 complementing gene codes for a putative protein kinase that is required for cell cycle arrest after DNA damage but not for the feedback control that links mitosis to the completion of prior DNA synthesis (the same gene has recently been described by Walworth et al. (1993) as chk1). These properties are similar to those of the rad9 gene of Saccharomyces cerevisiae. A comparative analysis of the radiation responses in rad26.d, rad26.T12, and rad27.d cells has revealed the existence of two separable responses to DNA damage controlled by the "checkpoint rad" genes. The first, G2 arrest, is defective in rad27.d and rad26.d but is unaffected in rad26.T12 cells. The second response is not associated with G2 arrest after DNA damage and is defective in rad26.d and rad26.T12 but not rad27.d cells. A study of the radiation sensitivity of these mutants through the cell cycle suggests that this second response is associated with S phase and that the checkpoint rad mutants, in addition to an inability to arrest mitosis after radiation, are defective in an S phase radiation checkpoint.
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Citations
Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint
Qinghua Liu,Saritha Guntuku,Xian Shu Cui,Shuhei Matsuoka,David Cortez,Katsuyuki Tamai,Guangbin Luo,Sandra Carattini-Rivera,Francisco J. DeMayo,Allan Bradley,Lawrence A. Donehower,Stephen J. Elledge +11 more
TL;DR: It is shown that in human cells, Chk1 is phosphorylated on serine 345 (S345) in response to UV, IR, and hydroxyurea (HU).
Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk regulation through Cdc25
Yolanda Sanchez,Calvin Wong,Calvin Wong,Richard S. Thoma,Richard S. Thoma,Ron Richman,Ron Richman,Zhiqi Wu,Zhiqi Wu,Helen Piwnica-Worms,Stephen J. Elledge,Stephen J. Elledge +11 more
TL;DR: Results suggest a model whereby in response to DNA damage, Chk1 phosphorylates and inhibits Cdc25C, thus preventing activation of the Cdc2-cyclin B complex and mitotic entry.
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ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.
Hui Zhao,Helen Piwnica-Worms +1 more
TL;DR: It is demonstrated that agents that block DNA replication or cause certain forms of DNA damage induce the phosphorylation of human Chk1, an evolutionarily conserved protein kinase that regulates cell cycle progression in response to checkpoint activation.
1.1K
Toward maintaining the genome: DNA damage and replication checkpoints.
TL;DR: The connection between checkpoint proteins and damage repair mechanisms, how cells recover from an arrest response, and additional roles that checkpoint proteins play in DNA metabolism are addressed.
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A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins.
TL;DR: A large super‐ family of domains that occur predominantly in proteins involved in cell cycle checkpoint functions responsive to DNA damage is revealed, likely to perform critical, yet uncharacterized, functions in the cell cycle control of organisms from bacteria to humans.
807
References
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Tamar Enoch,Paul Nurse +1 more
TL;DR: It is proposed that cdc25+ activity requires completion of earlier cell-cycle events such as DNA synthesis, and thus links p34cdc2 kinase activation to completion of these earlier events.
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TL;DR: Fission yeast mutants that enter mitosis when DNA replication is blocked with hydroxyurea are isolated and it is proposed that these genes participate in an intracellular signal transduction pathway that monitors the completion of DNA replication and transmits information to the mitotic control protein cdc2.