Reactome | CHEK1 is recruited to resected DNA DSBs

CHEK1 is recruited to resected DNA DSBs

Stable Identifier

R-HSA-5684882

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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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
15707391	DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system Clarke, PR, Clarke, CA	Biochem J	2005
16885023	Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress Li, L, Elledge, SJ, Wang, X, Hittelman, WN, Zou, L, Lu, T, Bao, S, Hurov, KE	Mol. Cell	2006
20233725	Tipin-replication protein A interaction mediates Chk1 phosphorylation by ATR in response to genotoxic stress Kaufmann, WK, Grillo, M, Yilmaz, S, Abraham, RT, Cordeiro-Stone, M, Sancar, A, Kang, TH, Kemp, MG, Akan, Z, Unsal-Kaçmaz, K, Smith-Roe, SL	J. Biol. Chem.	2010
22977173	Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress Troksa, K, Shrivastav, M, Amerin, C, Nickoloff, JA, Oakley, GG, Liu, S, Ashley, AK, Glanzer, JG, Manthey, K, Opiyo, SO	Nucleic Acids Res.	2012
21680713	Role for casein kinase 1 in the phosphorylation of Claspin on critical residues necessary for the activation of Chk1 Capalbo, L, Dunphy, WG, Meng, Z, Glover, DM	Mol. Biol. Cell	2011
12545175	Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1 Kumagai, A, Dunphy, WG	Nat Cell Biol	2003