ATM Gene Function
ATM Serine/Threonine Kinase
Overview
ATM is a master kinase activated by DNA double-strand breaks that phosphorylates hundreds of substrates to coordinate the DNA damage response, including cell cycle checkpoints and DNA repair.
Molecular Mechanism
Mechanism Summary
DNA double-strand breaks activate ATM via MRN-complex-mediated autophosphorylation at Ser1981, releasing ATM dimers into active monomers that phosphorylate >700 substrates to coordinate repair, checkpoints, and apoptosis.
Step-by-Step Mechanism
DSBs are detected within seconds by the MRN complex (MRE11 nuclease, RAD50 ATPase, NBS1 adaptor). MRN recruits ATM and stimulates its kinase activity through direct interaction with NBS1's ATM-binding motif.
ATM undergoes intermolecular autophosphorylation at Ser1981 (and Ser367, Ser1893), disrupting homodimer contacts and releasing active ATM monomers that spread along chromatin flanking the break.
ATM phosphorylates histone H2AX at Ser139 (γH2AX) within seconds over megabase domains flanking the break. γH2AX serves as a docking platform for MDC1, which amplifies ATM recruitment in a positive feedback loop.
ATM phosphorylates BRCA1 at Ser1387/Ser1423, promoting BRCA1 recruitment to DSBs and coordination of homologous recombination repair in S/G2 phase.
If damage is irreparable, sustained ATM/CHK2 signalling and p53 activation promote apoptosis or senescence rather than allowing a damaged cell to re-enter the cell cycle.
Upstream Regulators
Directly recruits ATM to DSBs and stimulates its kinase activity
Activate ATM in response to osmotic stress and replication stress without DSBs
Acetylates ATM Lys3016, required for full kinase activation at DSBs
Downstream Targets
DSB amplification scaffold
Checkpoint kinase cascade → G1/S, intra-S, G2/M arrest
HR repair initiation
p53 stabilisation → arrest or apoptosis
Key Post-Translational Modifications
Dimer disruption; monomerisation; kinase activation
Required for activation; TIP60 is activated by H4K16ac at DSBs
Regulates ATM protein stability and activity amplitude
Disease Mechanism
Biallelic pathogenic germline ATM variants cause ataxia-telangiectasia, which includes neurologic, immune and radiosensitivity phenotypes and increased cancer risk. Heterozygous germline and somatic tumour alterations raise different questions. ATM loss affects checkpoint signalling and is being studied with ATR, PARP and DNA-damaging strategies, but clinical sensitivity is not uniform and ATM status should not be treated as equivalent to BRCA1/2 deficiency.
Database References
Key Pathways
- ·DNA damage response
- ·ATM signaling pathway
- ·Cell cycle checkpoint
- ·Homologous recombination
Disease Associations
- ·Ataxia-telangiectasia
- ·Breast cancer predisposition
- ·Chronic lymphocytic leukemia
Research Activity
ATM is an actively studied target: about 75+ clinical trials that mention it are currently recruiting on ClinicalTrials.gov. Trial activity reflects research interest, not proven benefit — designs, endpoints and populations vary widely.
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Functional Partners
Common Questions About ATM
What does ATM do?
ATM is a master serine/threonine kinase activated by DNA double-strand breaks through the MRN complex (MRE11–RAD50–NBS1). Once active, it phosphorylates hundreds of substrates including H2AX, CHK2, BRCA1, and p53 to simultaneously activate DNA repair pathways and impose cell cycle checkpoints.
What disease is caused by ATM mutations?
Germline ATM mutations cause ataxia-telangiectasia (A-T), a rare autosomal recessive syndrome characterised by progressive cerebellar ataxia, oculocutaneous telangiectasias, immune deficiency, radiation hypersensitivity, and dramatically elevated cancer risk — particularly lymphomas and leukaemias.
What is ATM's role in cancer?
Somatic ATM mutations occur in ~15% of chronic lymphocytic leukaemias, mantle cell lymphoma, and prostate cancer. ATM loss impairs DNA damage response, allowing cells to accumulate mutations and also sensitising tumours to DNA-damaging chemotherapy and PARP inhibitors.
How does ATM activate p53?
ATM phosphorylates p53 at serine-15, disrupting its interaction with MDM2 and preventing ubiquitin-mediated degradation. ATM also phosphorylates CHK2, which reinforces p53 stabilisation through serine-20 phosphorylation. This kinase relay ensures rapid, robust p53 activation within minutes of DNA damage.