CHEK1 is recruited to resected DNA DSBs

Stable Identifier
R-HSA-5684882
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

The recruitment of CHEK1 (CHK1) to resected DNA double strand breaks (DSBs) and activation by ATR-mediated phosphorylation requires the presence of CLSPN (claspin) and TIMELESS:TIPIN protein complex. TIPIN simultaneously interacts with the RPA2 subunit of the RPA complex and CLSPN, allowing CLSPN to stably associate with resected DNA DSBs (Kemp et al. 2010). Phosphorylation of CLSPN at threonine T916 and serine S945 is needed for CHEK1 binding (Kumagai et al. 2003, Clarke and Clarke 2005). CLSPN phosphorylation at these sites is independent of CHEK1 (Bennett et al. 2008). Casein kinase 1 (CK1) was proposed as a kinase responsible for CLSPN phosphorylation (Meng et al. 2011) but the exact mechanism of this modification has not been established.

ATR-mediated phosphorylation of RAD17 on serine residues S635 and S645 is implicated in CLSPN recruitment to resected DNA DSBs and CLSPN phosphorylation (Wang et al. 2006). Also, phosphorylation of the RPA2 subunit of the RPA complex positively contributes to CHEK1 activation (Liu et al. 2012).

Literature References
PubMed ID Title Journal Year
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
15707391 DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system

Clarke, CA, Clarke, PR

Biochem J 2005
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
21680713 Role for casein kinase 1 in the phosphorylation of Claspin on critical residues necessary for the activation of Chk1

Meng, Z, Capalbo, L, Glover, DM, Dunphy, WG

Mol. Biol. Cell 2011
12545175 Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1

Kumagai, A, Dunphy, WG

Nat Cell Biol 2003
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