ATM

GeneName

ATM

Summary

ATM, or ataxia telangiectasia mutated, is a 351 kDa protein that plays a pivotal role in the cellular response to DNA damage. It is primarily localised in the nucleus, cytoplasm, and centrosome, and is involved in various essential processes such as DNA double-strand break repair, cell cycle regulation, and apoptosis. ATM functions as a serine/threonine kinase, activating numerous signalling pathways in response to DNA damage, including the p53-mediated pathway. It is also implicated in brain development and cellular responses to stress, such as gamma radiation and reactive oxygen species.

Importance

ATM is relevant to: - Cancer research due to its role in the DNA damage response and maintenance of genomic stability. - Neurodegenerative diseases, particularly ataxia-telangiectasia, where mutations in ATM lead to severe neurological symptoms. - Ageing studies, as it is involved in cellular senescence and lifespan determination. - Developmental biology, given its functions in heart and brain development, as well as meiotic processes.

Top Products

For researchers investigating ATM, we highly recommend the top-selling recombinant antibody, Anti-ATM antibody [Y170] (ab32420). This antibody has been validated in knockout models, ensuring reliable performance in various applications, including Western blotting (WB), immunocytochemistry (ICC), immunohistochemistry (IHC), and flow cytometry (FC). With 174 citations, it is well-regarded in the research community, making it an excellent choice for those seeking dependable detection of ATM.

Abcam Product Citation Summary

The data indicates that Abcam antibodies targeting ATM are predominantly used in human studies, particularly in the context of DNA damage response and cellular responses to radiation. The applications include Western blotting and immunofluorescence, highlighting the importance of ATM in various cellular processes such as apoptosis and pluripotency. Additionally, there is a focus on ATM's role in cancer research, particularly in pancreatic cancer and chronic radiation exposure.

Abcam Product Citation Table

Domain

The FATC domain is required for interaction with KAT5.

Function

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 (PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15064416, PubMed:15448695, PubMed:15456891, PubMed:15790808, PubMed:15916964, PubMed:17923702, PubMed:21757780, PubMed:24534091, PubMed:35076389, PubMed:9733514). Recognizes the substrate consensus sequence [ST]-Q (PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15448695, PubMed:15456891, PubMed:15916964, PubMed:17923702, PubMed:24534091, PubMed:9733514). Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism (By similarity). 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, FBXW7, FANCD2, NFKBIA, BRCA1, CREBBP/CBP, RBBP8/CTIP, MRE11, nibrin (NBN), RAD50, RAD17, PELI1, TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:10550055, PubMed:10766245, PubMed:10802669, PubMed:10839545, PubMed:10910365, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:21757780, PubMed:24534091, PubMed:26240375, PubMed:26774286, PubMed:30612738, PubMed:30886146, PubMed:30952868, PubMed:38128537, PubMed:9733515, PubMed:9843217). 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 (PubMed:19965871). Phosphorylates ATF2 which stimulates its function in DNA damage response (PubMed:15916964). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Phosphorylates TTC5/STRAP at 'Ser-203' in the cytoplasm in response to DNA damage, which promotes TTC5/STRAP nuclear localization (PubMed:15448695). Also involved in pexophagy by mediating phosphorylation of PEX5: translocated to peroxisomes in response to reactive oxygen species (ROS), and catalyzes phosphorylation of PEX5, promoting PEX5 ubiquitination and induction of pexophagy (PubMed:26344566).

Involvement in disease

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.

None

The disease is caused by variants affecting the gene represented in this entry.

Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.

Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).

Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.

Post-translational modifications

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:15790808, 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).

Sequence Similarities

Belongs to the PI3/PI4-kinase family. ATM subfamily.

Tissue Specificity

Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.

Cellular localization

• Nucleus
• Cytoplasmic vesicle
• Cytoplasm
• Cytoskeleton
• Microtubule organizing center
• Centrosome
• Peroxisome matrix
• Primarily nuclear (PubMed:9050866, PubMed:9150358). Found also in endocytic vesicles in association with beta-adaptin (PubMed:9707615). Translocated to peroxisomes in response to reactive oxygen species (ROS) by PEX5 (PubMed:26344566).

Alternative names

Serine-protein kinase ATM, Ataxia telangiectasia mutated, A-T mutated, ATM

Database links

swissprot:Q13315 omim:607585 entrezGene:472

Other research areas

• Epigenetics
• Immuno-oncology