ATM

The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM Serine/Threonine Kinase

Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:9843217, PubMed:9733515, PubMed:10550055, PubMed:10766245, PubMed:10839545, PubMed:10910365, PubMed:10802669, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:30612738, PubMed:30886146).
May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).

Brain development Source: Ensembl
Cell cycle arrest Source: BHF-UCL
Cellular response to DNA damage stimulus Source: UniProtKB
Cellular response to gamma radiation Source: CAFA
Cellular response to nitrosative stress Source: ParkinsonsUK-UCL
Cellular response to retinoic acid Source: ARUK-UCL
Cellular response to X-ray Source: ParkinsonsUK-UCL
Determination of adult lifespan Source: Ensembl
DNA damage checkpoint Source: GO_Central
DNA damage induced protein phosphorylation Source: UniProtKB
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Source: Reactome
DNA double-strand break processing Source: Reactome
DNA replication Source: Reactome
Double-strand break repair Source: Reactome
Double-strand break repair via homologous recombination Source: Ensembl
Double-strand break repair via nonhomologous end joining Source: Reactome
Establishment of protein-containing complex localization to telomere Source: BHF-UCL
Establishment of RNA localization to telomere Source: BHF-UCL
Female meiotic nuclear division Source: Ensembl
Heart development Source: Ensembl
Histone mRNA catabolic process Source: UniProtKB
Histone phosphorylation Source: InterPro
Intrinsic apoptotic signaling pathway in response to DNA damage Source: GO_Central
Lipoprotein catabolic process Source: Ensembl
Male meiotic nuclear division Source: Ensembl
Meiotic telomere clustering Source: Ensembl
Mitotic spindle assembly checkpoint Source: UniProtKB
Multicellular organism growth Source: Ensembl
Negative regulation of B cell proliferation Source: UniProtKB
Negative regulation of telomere capping Source: BHF-UCL
Negative regulation of TORC1 signaling Source: ParkinsonsUK-UCL
Neuron apoptotic process Source: Ensembl
Oocyte development Source: Ensembl
Ovarian follicle development Source: Ensembl
Peptidyl-serine autophosphorylation Source: MGI
Peptidyl-serine phosphorylation Source: UniProtKB
Pexophagy Source: Reactome
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of cell adhesion Source: ARUK-UCL
Positive regulation of cell migration Source: BHF-UCL
Positive regulation of DNA catabolic process Source: Ensembl
Positive regulation of DNA damage response, signal transduction by p53 class mediator Source: BHF-UCL
Positive regulation of gene expression Source: BHF-UCL
Positive regulation of histone phosphorylation Source: Ensembl
Positive regulation of neuron apoptotic process Source: Ensembl
Positive regulation of telomerase catalytic core complex assembly Source: BHF-UCL
Positive regulation of telomere maintenance via telomerase Source: BHF-UCL
Positive regulation of telomere maintenance via telomere lengthening Source: BHF-UCL
Positive regulation of transcription by RNA polymerase II Source: ARUK-UCL
Post-embryonic development Source: Ensembl
Pre-B cell allelic exclusion Source: UniProtKB
Protein autophosphorylation Source: BHF-UCL
Protein phosphorylation Source: UniProtKB
Reciprocal meiotic recombination Source: ProtInc
Regulation of apoptotic process Source: Reactome
Regulation of autophagy Source: ParkinsonsUK-UCL
Regulation of cellular response to gamma radiation Source: Ensembl
Regulation of cellular response to heat Source: Reactome
Regulation of microglial cell activation Source: Ensembl
Regulation of signal transduction by p53 class mediator Source: Reactome
Regulation of telomere maintenance via telomerase Source: BHF-UCL
Replicative senescence Source: BHF-UCL
Response to hypoxia Source: Ensembl
Response to ionizing radiation Source: UniProtKB
Signal transduction Source: ProtInc
Signal transduction involved in mitotic G2 DNA damage checkpoint Source: BHF-UCL
Somitogenesis Source: Ensembl
Telomere maintenance Source: GO_Central
Thymus development Source: Ensembl
V(D)J recombination Source: Ensembl

Nucleus; Cytoplasmic vesicle. Primarily nuclear. Found also in endocytic vesicles in association with beta-adaptin.

Ataxia telangiectasia (AT): A rare recessive disorder characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. Patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation.

Phosphorylated by NUAK1/ARK5 (PubMed:12409306). Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:21144835, PubMed:27664052). During the late stages of DNA damage response, dephosphorylated following deacetylation by SIRT7, leading to ATM deactivation (PubMed:30944854).
Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981 (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:17923702, PubMed:21144835). Acetylated in vitro by KAT5/TIP60 (PubMed:16141325). Deacetylated by SIRT7 during the late stages of DNA damage response, promoting ATM dephosphorylation and subsequent deactivation (PubMed:30944854).