Cds1 Phosphorylation by Rad3-Rad26 Kinase Is Mediated by Forkhead-associated Domain Interaction with Mrc1

Tanaka, Katsunori; Russell, Paul

doi:10.1074/jbc.m404834200

Cited by 34 publications

(35 citation statements)

References 49 publications

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“…In S. pombe, Mrc1 binding to the FHA domain is required for Cds1 activation by replication blocks (53). The following data indicate that this is not the case for S. cerevisiae Rad53.…”

Section: Fha1 Functions In the Mrc1 Pathwaymentioning

confidence: 70%

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

Pike

Tenis

Heierhorst

2004

Journal of Biological Chemistry

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Saccharomyces cerevisiae Rad53 has crucial functions in many aspects of the cellular response to DNA damage and replication blocks. To coordinate these diverse roles, Rad53 has two forkhead-associated (FHA) phosphothreonine-binding domains in addition to a kinase domain. Here, we show that the conserved N-terminal FHA1 domain is essential for the function of Rad53 to prevent the firing of late replication origins in response to replication blocks. However, the FHA1 domain is not required for Rad53 activation during S phase, and as a consequence of defective downstream signaling, Rad53 containing an inactive FHA1 domain is hyperphosphorylated in response to replication blocks. The FHA1 mutation dramatically hypersensitizes strains with defects in the cell cycle-wide checkpoint pathways (rad9⌬ and rad17⌬) to DNA damage, but it is largely epistatic with defects in the replication checkpoint (mrc1⌬). Altogether, our data indicate that the FHA1 domain links activated Rad53 to downstream effectors in the replication checkpoint. The results reveal an important mechanistic difference to the homologous Schizosaccharomyces pombe FHA domain that is required for Mrc1-dependent activation of the corresponding Cds1 kinase. Surprisingly, despite the severely impaired replication checkpoint and also G 2 /M checkpoint functions, the FHA1 mutation by itself leads to only moderate viability defects in response to DNA damage, highlighting the importance of functionally redundant pathways.

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“…In S. pombe, Mrc1 binding to the FHA domain is required for Cds1 activation by replication blocks (53). The following data indicate that this is not the case for S. cerevisiae Rad53.…”

Section: Fha1 Functions In the Mrc1 Pathwaymentioning

confidence: 70%

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

Pike

Tenis

Heierhorst

2004

Journal of Biological Chemistry

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“…We show here, together with previous studies (13,(21)(22)(23)(24), that five coordinated phosphorylations are required for efficient activation of the replication checkpoint. Analysis of the functional relation-ship between the phosphorylation events revealed a clear picture of the phosphorylation network required for activation of the replication checkpoint pathway in fission yeast.…”

mentioning

confidence: 97%

“…Rad3 and Cds1 are two major kinases in the replication checkpoint of S. pombe. Several phosphorylation sites on Mrc1, Rad9, and Cds1 have been identified by large scale mutational analyses and implicated for the activation of Cds1 (13,(21)(22)(23)(24)(25). However, whether these sites represent all phosphorylations required for Cds1 activation has been an unsolved issue.…”

mentioning

confidence: 99%

The Phosphorylation Network for Efficient Activation of the DNA Replication Checkpoint in Fission Yeast

Yue

Singh

Wang

et al. 2011

Journal of Biological Chemistry

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“…In fission yeast, two distinct checkpoints operate during different stages of the cell cycle to arrest cell cycle progression in response to DNA damage, or blocks to DNA replication. For example, in S phase, inhibition of replication fork progression by treatment with hydroxyurea (HU) leads to activation of the protein kinase Cds1, which delays G2 and stabilizes stalled replication forks (Lindsay et al, 1998;Alcasabas, 2001;Tanaka and Russell, 2001;Zhao et al, 2003;Tanaka and Russell, 2004;Zhao and Russell, 2004). Activation of Cds1 occurs downstream of the Rad-Hus signaling pathway that recognizes stalled forks and leads to activation of the ataxia-telangiectasia-mutated and ATM-and Rad3-related (ATM/ATR) homologue Rad3.…”

Section: Introductionmentioning

confidence: 99%

Activation of the DNA Damage Checkpoint in Mutants Defective in DNA Replication Initiation

Yin

Locovei

D’Urso

2008

MBoC

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In the fission yeast, Schizosaccharomyces pombe, blocks to DNA replication elongation trigger the intra-S phase checkpoint that leads to the activation of the Cds1 kinase. Cds1 is required to both prevent premature entry into mitosis and to stabilize paused replication forks. Interestingly, although Cds1 is essential to maintain the viability of mutants defective in DNA replication elongation, mutants defective in DNA replication initiation require the Chk1 kinase. This suggests that defects in DNA replication initiation can lead to activation of the DNA damage checkpoint independent of the intra-S phase checkpoint. This might result from reduced origin firing that leads to an increase in replication fork stalling or replication fork collapse that activates the G2 DNA damage checkpoint. We refer to the Chk1-dependent, Cds1-independent phenotype as the rid phenotype (for replication initiation defective). Chk1 is active in rid mutants, and rid mutant viability is dependent on the DNA damage checkpoint, and surprisingly Mrc1, a protein required for activation of Cds1. Mutations in Mrc1 that prevent activation of Cds1 have no effect on its ability to support rid mutant viability, suggesting that Mrc1 has a checkpoint-independent role in maintaining the viability of mutants defective in DNA replication initiation. INTRODUCTIONBefore cell division, all eukaryotic cells replicate their DNA through a highly regulated process that involves the binding of several proteins to origin DNA during the G1 phase of the cell cycle (Bell and Dutta, 2002;Diffley and Labib, 2002;Diffley, 2004). The first step in the initiation of DNA replication requires the binding of a six-member hetero-protein complex called Orc to replication origins, marking these sites for subsequent assembly of prereplicative complexes (pre-RCs). The assembly of pre-RCs is believed to occur in early G1, and it requires the loading of Mcm proteins to origin DNA. Two additional proteins Cdc18 and Cdt1 recruit Mcms to DNA and conversion of the pre-RC to an active initiation complex requires activation of both Cdk1 and Hsk1 kinases. Phosphorylation of key components of the pre-RC is believed to result in a reorganization of the origin-associated complex that allows the binding of additional replication proteins, including DNA polymerases and single-strand DNA binding protein. The Mcm complex, with its intrinsic ATPase activity, is believed to participate in the unwinding of DNA during DNA synthesis (Ishimi, 1997;Lee and Hurwitz, 2001).Analysis of cell cycle mutants in both Saccharomyces cerevisiae and Schizosaccharomyces pombe has led to the identification of a number of proteins that are involved in both the initiation and elongation of DNA replication. In addition to the previously mentioned Orc, Cdc18, Cdt1, and Mcm proteins, they include the Gins complex (Alberghina et al., 1983;Takayama et al., 2003;Gambus et al., 2006;Labib and Gambus, 2007), Sna41/Cdc45 (Miyake and Yamashita, 1998;Uchiyama et al., 2001a,b), Sld2, and Sld3 (Kamimura et al., 1998Nakajima an...

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Cds1 Phosphorylation by Rad3-Rad26 Kinase Is Mediated by Forkhead-associated Domain Interaction with Mrc1

Abstract: The protein kinase Cds1 is an effector of the replication checkpoint in the fission yeast Schizosaccharomyces pombe. Cds1 is required to stabilize stalled replication forks, and it helps to prevent the onset of mitosis until the genome is fully replicated.

Cited by 34 publications

References 49 publications

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

Rad53 Kinase Activation-independent Replication Checkpoint Function of the N-terminal Forkhead-associated (FHA1) Domain

The Phosphorylation Network for Efficient Activation of the DNA Replication Checkpoint in Fission Yeast

Activation of the DNA Damage Checkpoint in Mutants Defective in DNA Replication Initiation

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