ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks (canonical pathway), oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks.[5] It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.
In 1995, the gene was discovered by Yosef Shiloh[6] who named its product ATM since he found that its mutations are responsible for the disorder ataxia–telangiectasia.[7] In 1998, the Shiloh and Kastan laboratories independently showed that ATM is a protein kinase whose activity is enhanced by DNA damage.[8][9]
Throughout the cell cycle DNA is monitored for damage. Damages result from errors during replication, by-products of metabolism, general toxic drugs or ionizing radiation. The cell cycle has different DNA damage checkpoints, which inhibit the next or maintain the current cell cycle step. There are two main checkpoints, the G1/S and the G2/M, during the cell cycle, which preserve correct progression. ATM plays a role in cell cycle delay after DNA damage, especially after double-strand breaks (DSBs).[10] ATM is recruited to sites of double strand breaks by DSB sensor proteins, such as the MRN complex. After being recruited, it phosphorylates NBS1, along other DSB repair proteins. These modified mediator proteins then amplify the DNA damage signal, and transduce the signals to downstream effectors such as CHK2 and p53.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000149311 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034218 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Lee JH, Paull TT (December 2021). "Cellular functions of the protein kinase ATM and their relevance to human disease". Nature Reviews. Molecular Cell Biology. 22 (12): 796–814. doi:10.1038/s41580-021-00394-2. PMID 34429537. S2CID 237294441.
- ^ Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. (June 1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase". Science. 268 (5218): 1749–1753. Bibcode:1995Sci...268.1749S. doi:10.1126/science.7792600. PMID 7792600.
- ^ "Entrez Gene: ATM ataxia telangiectasia mutated (includes complementation groups A, C and D)".
- ^ Cite error: The named reference
pmid9733514was invoked but never defined (see the help page). - ^ Cite error: The named reference
pmid9733515was invoked but never defined (see the help page). - ^ Lee JH, Paull TT (December 2007). "Activation and regulation of ATM kinase activity in response to DNA double-strand breaks". Oncogene. 26 (56): 7741–7748. doi:10.1038/sj.onc.1210872. PMID 18066086.