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Replication checkpoint: tuning and coordination of replication forks in s phase.

Hustedt N, Gasser SM, Shimada K - Genes (Basel) (2013)

Bottom Line: During S phase, cells also provide a surveillance mechanism called the DNA replication checkpoint, which consists of a conserved kinase cascade that is provoked by insults that block or slow down replication forks.These can be exogenously induced or can arise from endogenous cellular activity.Here, we summarize the initiation and transduction of the replication checkpoint as well as its targets, which coordinate cell cycle events and DNA replication fork stability.

View Article: PubMed Central - PubMed

Affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. nicole.hustedt@fmi.ch.

ABSTRACT
Checkpoints monitor critical cell cycle events such as chromosome duplication and segregation. They are highly conserved mechanisms that prevent progression into the next phase of the cell cycle when cells are unable to accomplish the previous event properly. During S phase, cells also provide a surveillance mechanism called the DNA replication checkpoint, which consists of a conserved kinase cascade that is provoked by insults that block or slow down replication forks. The DNA replication checkpoint is crucial for maintaining genome stability, because replication forks become vulnerable to collapse when they encounter obstacles such as nucleotide adducts, nicks, RNA-DNA hybrids, or stable protein-DNA complexes. These can be exogenously induced or can arise from endogenous cellular activity. Here, we summarize the initiation and transduction of the replication checkpoint as well as its targets, which coordinate cell cycle events and DNA replication fork stability.

No MeSH data available.


Related in: MedlinePlus

Checkpoint signaling network. (A) Replication checkpoint signaling. The yeast equivalent to ATRIP, Ddc2, binds ssDNA that is covered with RPA, while the 9-1-1 checkpoint clamp is loaded onto ds/ssDNA junctions. Dpb11, 9-1-1, and Dna2 (checkpoint sensors, orange) can activate Ddc2-Mec1 (checkpoint kinase, purple). Checkpoint mediators like Mrc1 and Sgs1 (green) help activate Rad53 (checkpoint transducing kinase, blue). Rad53 activates Dun1 and other downstream responses. (B) DNA damage checkpoint signaling. Crosstalk between Mec1 and Tel1 (DSB response) can occur, if stalled replication forks collapse, since they can generate DSBs. These are resected to generate ssDNA which activates Mec1. Rad9, the DNA damage checkpoint mediator, can be recruited by histone modifications and also binds, once phosphorylated by CDK, to Dpb11. In addition, both Mec1 and Tel1 can activate the Chk1 kinase.
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genes-04-00388-f001: Checkpoint signaling network. (A) Replication checkpoint signaling. The yeast equivalent to ATRIP, Ddc2, binds ssDNA that is covered with RPA, while the 9-1-1 checkpoint clamp is loaded onto ds/ssDNA junctions. Dpb11, 9-1-1, and Dna2 (checkpoint sensors, orange) can activate Ddc2-Mec1 (checkpoint kinase, purple). Checkpoint mediators like Mrc1 and Sgs1 (green) help activate Rad53 (checkpoint transducing kinase, blue). Rad53 activates Dun1 and other downstream responses. (B) DNA damage checkpoint signaling. Crosstalk between Mec1 and Tel1 (DSB response) can occur, if stalled replication forks collapse, since they can generate DSBs. These are resected to generate ssDNA which activates Mec1. Rad9, the DNA damage checkpoint mediator, can be recruited by histone modifications and also binds, once phosphorylated by CDK, to Dpb11. In addition, both Mec1 and Tel1 can activate the Chk1 kinase.

Mentions: At the heart of all DNA damage checkpoint responses, are the two kinases Tel1 (telomere maintenance 1; ATM in mammals, see Table 1 for an overview of checkpoint protein names in several model organisms) and Mec1 (Mitosis Entry Checkpoint 1; ATR in mammals) (Figure 1) [3]. Both are phosphoinositide 3-kinase (PI3K)-related kinases (PIKKs) that share significant sequence homology and phosphorylate an overlapping set of substrates. Both show a preference for serine or threonine residues followed by glutamine ([S/T]Q) or a hydrophobic residue [13,14,15,16]. Often these target sites are found in SQ/TQ cluster domains (SCDs) [17]. All PIKKs, not only Mec1 and Tel1, share a common domain architecture in which the kinase domain is flanked by both FRAPP, ATM, TRRAP (FAT), and FAT C-terminal (FATC) domains (Figure 2A), all being conserved alpha-helical regions [18,19]. Because FAT and FATC domains are always present in combination, it has been suggested that these two domains interact with each other, potentially providing a scaffold or binding sites for other proteins [19].


Replication checkpoint: tuning and coordination of replication forks in s phase.

Hustedt N, Gasser SM, Shimada K - Genes (Basel) (2013)

Checkpoint signaling network. (A) Replication checkpoint signaling. The yeast equivalent to ATRIP, Ddc2, binds ssDNA that is covered with RPA, while the 9-1-1 checkpoint clamp is loaded onto ds/ssDNA junctions. Dpb11, 9-1-1, and Dna2 (checkpoint sensors, orange) can activate Ddc2-Mec1 (checkpoint kinase, purple). Checkpoint mediators like Mrc1 and Sgs1 (green) help activate Rad53 (checkpoint transducing kinase, blue). Rad53 activates Dun1 and other downstream responses. (B) DNA damage checkpoint signaling. Crosstalk between Mec1 and Tel1 (DSB response) can occur, if stalled replication forks collapse, since they can generate DSBs. These are resected to generate ssDNA which activates Mec1. Rad9, the DNA damage checkpoint mediator, can be recruited by histone modifications and also binds, once phosphorylated by CDK, to Dpb11. In addition, both Mec1 and Tel1 can activate the Chk1 kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924824&req=5

genes-04-00388-f001: Checkpoint signaling network. (A) Replication checkpoint signaling. The yeast equivalent to ATRIP, Ddc2, binds ssDNA that is covered with RPA, while the 9-1-1 checkpoint clamp is loaded onto ds/ssDNA junctions. Dpb11, 9-1-1, and Dna2 (checkpoint sensors, orange) can activate Ddc2-Mec1 (checkpoint kinase, purple). Checkpoint mediators like Mrc1 and Sgs1 (green) help activate Rad53 (checkpoint transducing kinase, blue). Rad53 activates Dun1 and other downstream responses. (B) DNA damage checkpoint signaling. Crosstalk between Mec1 and Tel1 (DSB response) can occur, if stalled replication forks collapse, since they can generate DSBs. These are resected to generate ssDNA which activates Mec1. Rad9, the DNA damage checkpoint mediator, can be recruited by histone modifications and also binds, once phosphorylated by CDK, to Dpb11. In addition, both Mec1 and Tel1 can activate the Chk1 kinase.
Mentions: At the heart of all DNA damage checkpoint responses, are the two kinases Tel1 (telomere maintenance 1; ATM in mammals, see Table 1 for an overview of checkpoint protein names in several model organisms) and Mec1 (Mitosis Entry Checkpoint 1; ATR in mammals) (Figure 1) [3]. Both are phosphoinositide 3-kinase (PI3K)-related kinases (PIKKs) that share significant sequence homology and phosphorylate an overlapping set of substrates. Both show a preference for serine or threonine residues followed by glutamine ([S/T]Q) or a hydrophobic residue [13,14,15,16]. Often these target sites are found in SQ/TQ cluster domains (SCDs) [17]. All PIKKs, not only Mec1 and Tel1, share a common domain architecture in which the kinase domain is flanked by both FRAPP, ATM, TRRAP (FAT), and FAT C-terminal (FATC) domains (Figure 2A), all being conserved alpha-helical regions [18,19]. Because FAT and FATC domains are always present in combination, it has been suggested that these two domains interact with each other, potentially providing a scaffold or binding sites for other proteins [19].

Bottom Line: During S phase, cells also provide a surveillance mechanism called the DNA replication checkpoint, which consists of a conserved kinase cascade that is provoked by insults that block or slow down replication forks.These can be exogenously induced or can arise from endogenous cellular activity.Here, we summarize the initiation and transduction of the replication checkpoint as well as its targets, which coordinate cell cycle events and DNA replication fork stability.

View Article: PubMed Central - PubMed

Affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. nicole.hustedt@fmi.ch.

ABSTRACT
Checkpoints monitor critical cell cycle events such as chromosome duplication and segregation. They are highly conserved mechanisms that prevent progression into the next phase of the cell cycle when cells are unable to accomplish the previous event properly. During S phase, cells also provide a surveillance mechanism called the DNA replication checkpoint, which consists of a conserved kinase cascade that is provoked by insults that block or slow down replication forks. The DNA replication checkpoint is crucial for maintaining genome stability, because replication forks become vulnerable to collapse when they encounter obstacles such as nucleotide adducts, nicks, RNA-DNA hybrids, or stable protein-DNA complexes. These can be exogenously induced or can arise from endogenous cellular activity. Here, we summarize the initiation and transduction of the replication checkpoint as well as its targets, which coordinate cell cycle events and DNA replication fork stability.

No MeSH data available.


Related in: MedlinePlus