Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint

Alan Yueh Luen Lee, Takuya Chiba, Lan N. Truong, An Ning Cheng, Johnny Do, Michael Jeffrey Cho, Longchuan Chen, Xiaohua Wu

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.

Original languageEnglish
Pages (from-to)2531-2543
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
Publication statusPublished - 2012 Jan 20
Externally publishedYes

Fingerprint

S Phase Cell Cycle Checkpoints
Ataxia Telangiectasia
Phosphotransferases
Phosphorylation
Proteins
DNA
Cells
DNA Replication
Ionizing radiation
Chemical activation
Licensure
Ionizing Radiation
S Phase
DNA Damage
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint. / Lee, Alan Yueh Luen; Chiba, Takuya; Truong, Lan N.; Cheng, An Ning; Do, Johnny; Cho, Michael Jeffrey; Chen, Longchuan; Wu, Xiaohua.

In: Journal of Biological Chemistry, Vol. 287, No. 4, 20.01.2012, p. 2531-2543.

Research output: Contribution to journalArticle

Lee, Alan Yueh Luen ; Chiba, Takuya ; Truong, Lan N. ; Cheng, An Ning ; Do, Johnny ; Cho, Michael Jeffrey ; Chen, Longchuan ; Wu, Xiaohua. / Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 4. pp. 2531-2543.
@article{e4bbdd7772d0409cac6563ac4dd30552,
title = "Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint",
abstract = "Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.",
author = "Lee, {Alan Yueh Luen} and Takuya Chiba and Truong, {Lan N.} and Cheng, {An Ning} and Johnny Do and Cho, {Michael Jeffrey} and Longchuan Chen and Xiaohua Wu",
year = "2012",
month = "1",
day = "20",
doi = "10.1074/jbc.M111.291104",
language = "English",
volume = "287",
pages = "2531--2543",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "4",

}

TY - JOUR

T1 - Dbf4 is direct downstream target of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) protein to regulate intra-S-phase checkpoint

AU - Lee, Alan Yueh Luen

AU - Chiba, Takuya

AU - Truong, Lan N.

AU - Cheng, An Ning

AU - Do, Johnny

AU - Cho, Michael Jeffrey

AU - Chen, Longchuan

AU - Wu, Xiaohua

PY - 2012/1/20

Y1 - 2012/1/20

N2 - Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.

AB - Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.

UR - http://www.scopus.com/inward/record.url?scp=84862972549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862972549&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.291104

DO - 10.1074/jbc.M111.291104

M3 - Article

C2 - 22123827

AN - SCOPUS:84862972549

VL - 287

SP - 2531

EP - 2543

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 4

ER -