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#Chk2

2 public questions tagged with this topic.

Cell Cycle Regulation

The primary function of Chk2 in DNA damage response is to:

Double-strand breaks caused by ionizing radiation or replication collapse activate upstream kinase ATM, recruited and stimulated by MRN complex bound to broken ends. Active ATM phosphorylates histone variant H2AX at Ser139 forming gamma-H2AX domains that recruit mediator proteins Mdc1, 53BP1 and effector kinase Chk2 through its FHA domain. ATM phosphorylates Chk2 at Thr68 within N-terminal SQ/TQ cluster, promoting dimerization via FHA domain exchange and autophosphorylation at Thr383/Thr387 in activation loop, yielding fully active kinase. Chk2 phosphorylates numerous downstream substrates, most notably tumor suppressor p53 at Ser20 within N-terminal transactivation domain, disrupting interaction with E3 ligase Mdm2 and stabilizing p53 tetramers. Accumulated p53 induces transcription of cyclin dependent kinase inhibitor p21, GADD45, 14-3-3 sigma and proapoptotic Bax, Puma, Noxa, producing G1/S and G2/M arrest or apoptosis depending on damage severity. Chk2 also phosphorylates Cdc25A, BRCA1 Ser988 facilitating homologous recombination, and PML, integrating break detection with transcriptional DNA damage program for genome preservation. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Bartek et al., Chk2 Kinase and p53 After DNA Damage, Nat Rev Mol Cell Biol 2001; NCBI Bookshelf, ATM-Chk2-p53 Signaling.

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Cell Cycle Regulation

Which checkpoint kinase ensures DNA integrity before mitosis?

Genome surveillance employs two parallel transducer kinases converging on cell cycle arrest before mitosis. ATR-Chk1 pathway responds primarily to single-stranded DNA, stalled forks, base adducts and resected double-strand break ends processed by Exo1 and CtIP nucleases. ATM-Chk2 pathway recognizes blunt double-strand breaks via MRN complex Mre11-Rad50-Nbs1 mediated ATM recruitment and activation at break sites. Activated ATR phosphorylates Chk1, while ATM phosphorylates Chk2 at Thr68 promoting dimerization and full activation through autophosphorylation at Thr383 Thr387 in activation loop. Both Chk1 and Chk2 phosphorylate Cdc25A targeting Thr504 for ubiquitination, Cdc25B and C, creating 14-3-3 docking sites that inactivate phosphatases, thus maintaining CDK1 phosphorylated at Thr14-Tyr15 in inactive state. They also phosphorylate p53 at Ser20 disrupting Mdm2 interaction, stabilizing tumor suppressor to induce p21, GADD45 and 14-3-3 sigma for sustained arrest. Additionally, they phosphorylate BRCA1, Rad51 and histone H2AX, coordinating repair pathway choice with cell cycle delay, preventing transmission of damaged chromosomes into mitosis and preserving genome stability across divisions. Additional feedback loops involving polo-like kinases, phosphatases and SCF-mediated degradation reinforce irreversibility and protect against premature progression that would compromise genome integrity and viability.

Ref: Bartek & Lukas, Chk1 and Chk2 checkpoint kinases, Cancer Cell 2003; NCBI Bookshelf, G2/M DNA Damage Checkpoint.

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