DNA IR-Double Strand Breaks (DSBs) and cellular response via ATM (Homo sapiens)

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28, 76110, 143, 305, 3322, 50, 146, 204, 24766, 81, 257107, 229, 334, 39278, 100, 159, 206, 215...71, 162, 324188230, 352, 390363196, 25828532321629306851647833528428937292281289190, 198, 34756, 28332227033, 4363, 191, 195, 297149, 21032816027, 102, 145, 189, 222...18764, 314223, 336, 35319998, 35531, 175167139, 248349298, 40736934, 60, 31128, 76138, 2622173865153, 1861643153996, 3853572185338864412243, 258, 36342625070133, 33727998, 260, 36444, 27017, 18482921833095, 156, 30978160, 197, 36536, 29232, 168, 256, 290, 331306205, 28775, 2423579, 382339, 3453053, 37030933096, 193, 232414Inhibition pathNuA4complexDNA DSBsIonizing Radiation (IR)ATM-TRAF6-cIAP1module21, 25, 63, 144, 174...12, 200, 207, 213, 249...CDK5UPF1BRCA2APAF1NFkB activationRAD51RASSF1PARP1MDC1ACTL6ACHK2BRCA1DCLRE1CSMC3E2F1MDM2The intra-S-phasecheckpoint mediatedarrest of cell cycleprogressionTP53OBFC2BRAD52ApoptosisBAK1NBNTERF2SMC1AM-Phase ProgressionBLMPCNABAXMRE11AARF(CDKN2A)ATRDNA-PKTRAF6ATMMCPH1STK3mRNA nonsense-mediateddecay (NMD)HSF1TRIM28EXO1LATS1RAD50CohesinCASP9KAT5p73CHK1RAD17TP53BP1MCPH173, 177, 243, 302, 391...120, 254, 35024, 72, 112, 116, 148...180, 238, 295, 423129, 294, 317, 37848, 116, 169, 276, 2776, 172, 214, 280, 41351, 344, 38945, 296, 319, 348221, 339, 380154, 235, 25388, 131, 272, 377, 415...20, 23, 103, 219, 243...11, 69, 23998, 260, 310, 355, 364...62, 115, 130, 304, 316153, 159, 16499, 226, 340, 395211, 268, 371, 37218, 83, 124, 134, 137...5, 52, 282, 318, 320...16, 84, 135, 147, 288...22, 308, 312165, 356, 358, 39611, 114, 241, 379, 40514, 58, 152, 410159173, 230, 352236, 354, 43741, 55, 118, 126, 158...108, 132, 212, 264, 3659, 149, 210, 361, 382...42013, 300, 402, 43837, 141, 24547, 125, 140, 171, 237...178, 324, 373, 411133, 337, 34914, 49, 152, 412205, 259, 287, 38791, 109, 157, 2748, 42, 99, 111, 160...113, 343, 41789, 275, 303, 342, 4254, 220, 321, 401PATM38, 43, 59, 93, 121...PBID74, 233, 419RAD9A80, 327H2AX1, 67, 105, 166, 176...DNA Repair15, 234, 267, 381, 429PAPAF1CASP9CASP37, 35, 54, 333, 416...RNF865, 299, 306RIF1202, 291, 292Cell CycleCheckpoint Activation101, 136, 246, 397, 399G2/M-Phase Checkpoint122, 150, 394Damage ProcessingDNA Polymerasedelta tetramer251, 40877, 261, 424Member of the groupIntermediate paths not shownPath to processStimulation pathRelation to pathRelation to path(intermediate steps not shown)CDC25C46, 90, 225Translocation pathATMTRAF6Cell Survival255ABL196, 104, 117, 346ACTL6AKAT53602653MDM2ARF(CDKN2A)Cell cycle arrestat G1 & G2ARF-MD2McomplexATF2123, 155, 27111, 69, 23919, 30478188188MRE11ARAD50NBNGammaH2AXMDC1MRNcomplex86194YAP126, 106, 228, 375FANCD210, 57, 79, 97, 182...7, 61, 87, 94, 119...65, 299, 306, 328, 422FANCD1FANCD1BRCA2128, 358, 39613468, 286, 293217


Description

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.

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Bibliography

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