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#ATM

3 public questions tagged with this topic.

Cell Cycle Regulation

Which kinase phosphorylates Chk1 in response to replication stress?

Replication stress exposes extended single-stranded DNA regions coated by replication protein A, forming a key signaling platform. ATR kinase, recruited via ATRIP-interacting domain to RPA-ssDNA, is the principal sensor of this structure. At stalled forks, factors TopBP1, Claspin, Timeless-Tipin and Rad9-Rad1-Hus1 clamp augment ATR activation through direct binding and allosteric stimulation. Once activated, ATR directly phosphorylates checkpoint kinase Chk1 on serine residues 317 and 345 within its C-terminal regulatory domain. This modification relieves autoinhibition, enabling Chk1 catalyti

Ref: Cimprich & Cortez, ATR role in replication checkpoint, Nat Rev Mol Cell Biol 2008; NCBI Bookshelf, Replication Stress Response.

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Cell Cycle Regulation

Which DNA repair pathway is activated by ATM after detecting double-strand breaks?

Double-strand breaks present challenging repair choice between rapid but error-prone non-homologous end joining and accurate homologous recombination available only when sister chromatid present. ATM kinase activated by MRN complex phosphorylates H2AX, creating gamma-H2AX domains that recruit mediator 53BP1, which in turn favors end joining by blocking resection. In G1 phase when homologous template absent, ATM-53BP1 axis directs breaks toward classical non-homologous end joining pathway that directly ligates ends after minimal processing by Ku70/Ku80 heterodimer, DNA-PKcs, and XRCC4-DNA ligas

Ref: Marechal & Zou, Genes Dev 2013, DNA Damage Response; Scully et al., Cell 2019, DSB Repair Choice.

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Cell Cycle Regulation

Which kinase is activated in response to double-strand DNA breaks?

DNA double-strand breaks are among most deleterious lesions, potentially generating chromosomal translocations if unrepaired. Detection relies on sensor complex MRN composed of Mre11, Rad50, and Nbs1 that binds broken ends and recruits serine/threonine kinase ATM, ataxia telangiectasia mutated, member of PI3K-like kinase family. ATM exists as inactive dimer; upon recruitment and interaction with Nbs1 C-terminus, it autophosphorylates at serine 1981, dissociates into active monomers, and phosphorylates hundreds of targets including histone variant H2AX at serine 139 forming gamma-H2AX foci that

Ref: Abraham, Genes Dev 2001, ATM and ATR Kinases; Shiloh & Ziv, Nature Rev Mol Cell Biol 2013, ATM Signaling.

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