Wide-ranging correlations are found between the initial physical features of radiation exposure and the possibility of biological consequences. These persist even with the chain of physical, chemical and biological processes that eliminate the majority of the early damage. Ionizing radiations (IRs) generate hundreds of different simple chemical products in DNA as well multitudes of clustered combinations. The simple products, including single-strand breaks (SSBs), tend to correlate poorly with biological effectiveness. However, when IR produce double-strand breaks (DSBs) in DNA it comes a large rise in relative biological response to cellular damage. In general terms, IRs produce a wide variety of DNA lesions and DSBs are considered to be the major actor responsible for cell death. If unrepaired or improperly repaired, DSBs contribute to chromosomal aberrations, which may lead to human disorders including cancer. The accurate preservation of chromosome continuity in human cells during either DNA replication or repair is critical for preventing the conversion of normal cells to an oncogenic status. The production of DSBs can be quantified by biochemical techniques, e.g., pulsed field gel electrophoresis (PFGE) and cell imaging, either globally or damage specific, through immunostaining of marker proteins or recruitment of fluorescent proteins to the DNA breaks. In vertebrate cells, the elimination of DSBs with minimal nucleotide sequence change involves the spatiotemporal orchestration of an apparently endless number of proteins ranging, according to their action, from the nucleotide level to nucleosome organization and chromosome architecture. DSBs trigger a multitude of post-translational modifications that alter both, catalytic activities and the specificity of protein interactions including: phosphorylation, methylation, ubiquitylation, acetylation, and SUMOylation, followed by the turnaround of these changes as repair has been completed. In mammalian cells, the formation of DSBs initiates a massive global cellular response, either checkpoint signaling and repair or cell death (apoptosis). A major role is that of the MRN (MRE11/RAD50/NBS1) complex binding to DSBs and facilitating the activation of ATM (Ataxia Telangiectasia Mutated) protein, a key PI3K (Phosphatidylinositol 3-kinase) related kinase in the DNA damage response (DDR). At the break site, ATM autophosphorylates, allowing its activation and the following phosphorylation of several substrates in the surrounding chromatin. The following pathway diagrams the early events of the cellular response after DSBs by IR through the activation of ATM in human cells. ff8 a14 From Pathway: SPIKE 00003 ba8 d94 e23 b71 a9a e86 bdd ee0 cf1 ca8 ec7 b64 c21 f42 da0 e53 df7 a45 e47 f08 f0a eb0 b72 a52 ad1 Q92993 is the catalytic subunit of the NuA4 histone acetyltransferase complex. dd1 b7f f80 aab f93 f48 ede a6b d92 ef7 e1c be9 d41 cce b03 ee7 e1c c10 fc1 ae0 bf6 a3f d6b c40 b08 c45 f28 c2e b48 c7e c57 e7d f40 c98 d1c d1d a53 ed9 ee8 d56 bbd fe8 f27 b87 f75 fae a28 b7f f24 bfa f76 c46 b5c d01 a2e c4f c39 dd7 e1a e01 db2 d4c d71 f19 e8c ce4 ebe fe7 f90 ff5 f8f b84 bbe a44 e31 c28 a95 a77 b5b cff bac c44 f06 efa ea7 b6a ed6 bc7 c80 e34 e1b e32 dbe de5 f8a f03 f7a ccd d55 d65 a51 e8d ec5 c3a ccf a08 bc2 c40 e03 eca f73 eab c45 e7f f40 d37 d1c e23 c66 b9c c23 a70 d24 afd acc c1d f37 b40 acb b21 db4 b1c fb9 b39 bba a11 a0b c92 a5a b99 aca a58 cfd dc2 fb8 b67 ef3 f31 d47 b8b c0d f7e f24 f00 fea bb1 d03 f67 e2d af6 d80 fa7 d67 ac8 fb4 a61 aa4 ba3 b6c ad4 db7 bec ea6 e4c e82 def e56 ea2 c6c d84 edc b9f d11 b8f d2d ce7 d99 f3f e9a b6f e45 d5d ff0 f0b f9c d9f fe6 cef ad2 eaa b9e b5d a8b ea3 b2b b59 d9e af7 dcb f7d a60 b22 e00 cc3 e72 d44 a7c a84 c8b bd1 fa2 b81 ab2 a3b f3a aa5 dc3 e69 cda e05 ad5 b0f bbc f50 fba c30 f8b c65 ff6 caf Q92993 is the catalytic subunit of the NuA4 histone acetyltransferase complex. c74 bc1 be8 a7f b44 a7e cc1 a5b dd0 bca c0c b55 b2f c47 dd3 be2 cc6 aaf f2b bba a11 a14 ff8 fd0 f43 fe2 d48 ff6 db0 c48 a0e f8d f0f c84 caa c7f d58 bdf d8b fe5 fa2 a76 c9b ab8 bc7 c80 cf5 da1 ed6 dd1 e14 fb8 a84 d76 d87 c02 e03 aca b99 e48 fde bf5 dd1 fa5 e75 ccc f23 a18 e25 eff fa7 e03 ffe b84 f8f a84 e3f ac8 d5f a0e a5c f3e fa5 acb d7e a30 e31 bbe c2d ded b27 bb6 a02 d76 dea b99 c92 a0b dfc c5a ed4 dab ea1 ded e0b cc0 f71 cbb d76 f17 a6f cec e10 c72 d19 b5f d04 d4f bae c79 ea0 fd2 c61 d3d ea9 de2 cdc c2d a9a b71 fa2 e7d bf5 bb6 e1c f18 ea1 f4c efe a86 b06 d9c ac3 bdf ba5 e54 af1 ff6 b39 e55 bcf ad8 d4a c6f dd6 e63 b01 ccc cc9 b0b a52 c77 a42 a39 d60 ff7 c59 f29 f0f ba8 e23 d94 fae d6c bdf d8b d8b e93 b45 f70 af3 d44 cba fcc fc9 fb5 d5e a84 ae2 c02 bd1 c8b b48 c2e e5c aa4 bd2 b57 a96 f2b d22 dc5 c94 d6f fbe cdb f57 d82 cd4 b60 ba6 fc0 c18 e9e d09 fdc ca3 d86 fd5 aed c4c b9b ac1 c99 d05 c75 d66 a32 ad9 f0d c56 d96 b70 be4 b7f bf7 bdf e4d df1 a13 c0a d8d disease of cellular proliferation DOID:14566 Human Disease Ontology altered programmed cell death pathway PW:0001559 Pathway Ontology altered double-strand DNA repair pathway PW:0000667 Pathway Ontology pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis PW:0000085 Pathway Ontology 10464290 PubMed Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. 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