Activation of CHEK1 at resected DNA DSBs

Stable Identifier
R-HSA-5684887
Type
Reaction
Species
Homo sapiens
Compartment
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Summation

CHEK1 (Chk1) is a checkpoint kinase activated during genotoxic stress. CHEK1 activation at resected DNA double strand breaks (DSBs) involves ATR-mediated phosphorylation of CHEK1 serine residues S317 and S345 in the presence of claspin (CLSPN), TOPBP1, RAD17:RFC complex, RAD9:HUS1:RAD1 complex, TIMELESS:TIPIN complex, RPA complex and RHNO1 (Liu et al. 2000, Zhao and Piwnica-Worms 2001, Kumagai and Dunphy 2003, Sorensen et al. 2004, Wang et al. 2006, Kemp et al. 2010, Cotta-Ramusino et al. 2011, Liu et al. 2012). Following phosphorylation, CHEK1 dissociates from chromatin and phosphorylates target proteins involved in S/G2 checkpoint activation and/or homologous recombination repair (Smits et al. 2006). CLSPN needs to interact with chromatin only transiently in order to facilitate CHEK1 activation (Lee et al. 2005).

Literature References
PubMed ID Title Journal Year
16148040 Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response

Lee, J, Gold, DA, Shevchenko, A, Shevchenko, A, Dunphy, WG

Mol Biol Cell 2005
10859164 Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.

Liu, Q, Guntuku, S, Cui, XS, Matsuoka, S, Cortez, D, Tamai, K, Luo, G, Carattini-Rivera, S, DeMayo, F, Bradley, A, Donehower, LA, Elledge, SJ

Genes Dev 2000
16885023 Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress

Wang, X, Zou, L, Lu, T, Bao, S, Hurov, KE, Hittelman, WN, Elledge, SJ, Li, L

Mol. Cell 2006
20233725 Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress

Kemp, MG, Akan, Z, Yilmaz, S, Grillo, M, Smith-Roe, SL, Kang, TH, Cordeiro-Stone, M, Kaufmann, WK, Abraham, RT, Sancar, A, Unsal-Kaçmaz, K

J. Biol. Chem. 2010
22977173 Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress

Liu, S, Opiyo, SO, Manthey, K, Glanzer, JG, Ashley, AK, Amerin, C, Troksa, K, Shrivastav, M, Nickoloff, JA, Oakley, GG

Nucleic Acids Res. 2012
15190204 ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage

Sorensen, CS, Syljuasen, RG, Lukas, J, Bartek, J

Cell Cycle 2004
11390642 ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1

Zhao, H, Piwnica-Worms, H

Mol Cell Biol 2001
21659603 A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling

Cotta-Ramusino, C, McDonald, ER, Hurov, K, Sowa, ME, Harper, JW, Elledge, SJ

Science 2011
16360315 Rapid PIKK-Dependent Release of Chk1 from Chromatin Promotes the DNA-Damage Checkpoint Response

Smits, VA, Reaper, PM, Jackson, SP

Curr Biol 2006
12545175 Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1

Kumagai, A, Dunphy, WG

Nat Cell Biol 2003
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Event Information
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Catalyst Activity
Catalyst Activity
Title
protein serine/threonine kinase activity of ATR:ATRIP:p-RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1:TIMELESS:TIPIN:p-T916,S945-CLSPN:CHEK1 [nucleoplasm]
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Orthologous Events
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