DNA IR-damage and cellular response via ATR (Homo sapiens)

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43, 90, 188, 266, 327...283, 297, 633663121, 66552017, 88, 126, 441, 69718096, 315, 695204, 58159756475824694611217, 341, 451, 482, 67992652449, 509170, 205, 208454373433374657505697101, 347, 4548219426068574, 657665, 67445034426663429483580282, 4541941763650, 210, 250, 254, 317...8518, 330, 70836236211734717181412, 556, 57412, 80366, 612672139236552163334150597, 60447521229, 6656066826436115335165535232270672234595260Ionizing Radiation (IR)ATR-ATRIPcomplexDNA DSBsLegend:86, 244, 364, 402, 421...90, 104, 163, 282, 493...21, 359, 391, 399, 510...CHK1The intra-S-phasecheckpoint mediatedarrest of cell cycleprogressionDCLRE1ARAD51EXO1FANCARFWD3SP1USP1MUTL-ALPHAMLH1BRCA1PCNATDP1MDM2RAD9SMC1AMDC1FANCIPOLNBCL6MCPH1RAD52M-Phase ProgressionTP53XRCC5BRCA2PRKDCTRIM28SMARCC2MRE11ATP53BP1RAD50ssDNARAD17CLK2UB2D3MCM2ATRHERC2PLK1PPM1DBLMIKPKBRPA2CEP164MCPH1SMARCAL1E2F1MSH2POLBUPF1EEF1E1CLSPNXPARBBP8NBNCHK244, 174, 343, 357, 420...96, 315, 695139, 216, 221, 338, 381...7, 22, 258, 702115, 213, 721331, 515, 53234, 37, 172, 236, 269...136, 286, 464, 492, 559...13, 385, 41341, 201, 232, 326, 417...2, 22, 105, 238, 294...19, 23, 80, 242, 72337127, 46, 79, 335, 461...109, 304, 6079, 58, 65, 111, 131...157, 222, 442, 462, 60054, 257, 276, 426, 564...170, 205, 208, 266, 535...112, 28010, 35, 60, 116, 382...380, 595, 61811, 146, 168, 176, 247...206, 212, 225, 319, 475161, 257, 264, 279, 404...128, 609, 63115, 67, 186, 274, 416...460, 657, 67114, 114, 166, 277, 349...93, 308, 377, 436, 502315, 424, 432, 554, 626143, 203, 320, 428, 434...91, 453, 508, 698, 727129, 156, 207, 281, 342...70, 211, 302, 318, 472...66, 175, 307124, 291, 466, 489, 538...36990, 188, 196, 266, 388...61, 394, 690153, 218, 230, 367, 623...97, 120, 198, 303, 41425, 165, 31138, 74, 145, 147, 177...285, 368, 425, 506, 52642, 100, 389, 5653, 6, 30, 72, 167...310, 582, 635258, 263, 702, 70331, 63, 316, 323, 352...64, 75, 77, 83, 209...73, 140, 154, 415, 418...113, 140, 409, 498, 616293, 332, 707, 713PATM23, 171, 190, 370, 444...H2AX102, 142, 259, 296, 355...DNA Repair55, 192, 215, 645, 647RNF817, 88, 126Cell CycleCheckpoint Activation28, 284, 339, 401, 714G2/M-Phase Checkpoint40, 53, 490Damage ProcessingDNA Polymerasedelta tetramer62273, 340, 463CDC25C26, 98, 378MRE11ARAD50NBNGammaH2AXMDC1MRNcomplex151, 241, 278, 704FANCD2FANCD2108, 123, 363, 400, 447...BRCA2107, 124, 379, 474, 481...UIMC145, 144, 169, 185, 197...TOPBP1PML84, 87, 228, 262, 282...4, 33, 76, 103, 127...RPA120, 48, 90, 119, 216...BRIP1268, 361, 512, 661, 676RAD151, 125, 184, 236, 500HUS1269, 301, 348, 387, 500...BARD1173, 465, 578, 589, 625BRCC3346, 405, 654FAM175ACDC45169, 224, 328, 333, 617...RECQL5117, 134, 180, 251, 299...WRN122, 199, 300, 321, 517...219, 246, 267, 468, 590...RECQL449, 57, 89, 354, 435...RECQLRMI124, 69, 272, 403, 485...TOP3A149, 233, 602182, 295, 298, 479, 511...PARP1ssDNA183, 271, 467, 478, 496...RPA1ATRIP5, 90, 163, 312, 493...RAD9RAD1HUS19-1-1complex51, 133, 235, 236, 269...26013559739332SHFM1634FOXM1110, 214, 253, 353, 375...PALB2161, 406, 40781, 158, 164, 195, 200...CycA59, 94, 159, 162, 234...Cdk2CycB8, 106, 148, 191, 358...Cdc299, 152, 231, 256, 324...G1/S boundary activation118, 240, 290, 360, 452...FEN116, 138, 187, 226, 431...BARD1UIMC1BRCA1UIMCI-BRCA1-BARD1complex597RBBP8BLM10, 35, 60, 116, 523...RMI1TOP3ABLMcomplexRecQ-like helicasesInhibition pathMember of the groupIntermediate paths not shownPath to processStimulation pathRelation to pathRelation to path(intermediate steps not shown)Translocation pathCycACdk2CycBCdc2ATRATRIPCellular responseto DNA damage


Description

In fission yeast, the rad3 gene product plays a critical role in sensing DNA structure defects and activating damage response pathways. A structural homologue of rad3 in humans has been identified based on sequence similarity in the protein kinase domain. ATR (for Ataxia Telangiectasia and Rad3-related) is considered the mammalian counterpart of yeast rad3, Mec1p, and fruit fly Mei-41, proteins involved in DNA damage responses.

The ATR protein is a member of the phosphoinositide 3-kinase related kinase family and plays an important role in UV-induced DNA damage checkpoint response and its role as a signal transducer in cell cycle checkpoint has been well established. Even though it is currently unclear whether ATR functions as a damage sensor, recent evidence shows that ATR may function as an initial sensor in the DNA damage checkpoint response. Moreover, it has been found that ATR is a DNA—binding protein with higher affinity to UV-damaged than undamaged DNA. In addition, damaged DNA stimulates the kinase activity of ATR to a significantly higher level than undamaged DNA. ATR is structurally related to ATM (for Ataxia Telangiectasia Mutated) as well as the yeast PIK family members Mec1p and Rad3. Mec1p and Rad3 participate in checkpoint pathways induced by DNA replication blocks, DNA strand breaks, and other chromosomal abnormalities, which implies that ATR performs similar functions in mammalian cells. Reports have demonstrated that overexpression of a catalytically inactive version of ATR (ATRki) in human fibroblasts caused hypersensitivity to gamma-radiation and hydroxyurea and abrogation of the radiation—induced G2 checkpoint. The checkpoint defects observed in ATRki—overexpressing cells resemble those found in AT cells. Additionally, ATR functions as an upstream regulator of p53 phosphorylation in DNA—damaged cells. ATR phosphorylates p53 at both Ser-15 and Ser-37 in vitro, suggesting that ATR is directly involved in the modification of p53 in DNA-damaged cells. Recent reports concerning ATM, suggest that ATR and ATM play both overlapping and independent roles in the phosphorylation of p53 during cellular exposure to genotoxic stress. Atr is localized to the nuclei of primary spermatocytes, cells that are undergoing meiosis I. It has been demonstrated that both Atr and Atm proteins have associated protein kinase activity, consistent with their primary structures. Additionally, Atr and Atm show specific association with chromosomes in cells that are in early meiosis I as demonstrated by antibody localization on surface—spread spermatocytes. Both the Atr and Atm proteins are present at pairing forks in meiotic prophase as chromosomes synapse; however, they do not colocalize, instead they occupy complementary positions: Atr localizes along unsynapsed chromosome axes and Atm interacts with synapsed axes.

Meanwhile ATM is activated by damage-induced rapid intermolecular autophosphorylation prior relocalization to sites of DNA breaks, ATR activation seems to require single-stranded DNA (ssDNA) coated with replication protein A. The recruitment of ATR to damage sites appears to be mediated by an ATR-interacting protein that forms a stable complex with the vast majority of ATR in human cells.

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History

View all...
CompareRevisionActionTimeUserComment
120667view00:23, 23 December 2021EweitzStandardize font, weight, case
119294view11:20, 23 June 2021FinterlyRemoved empty Biopax and corresponding BiopaxRefs
108188view10:55, 29 November 2019FehrhartOntology Term : 'cancer' added !
101923view16:07, 17 November 2018EgonwRemoved whitespace in PubMed identifiers.
101837view16:45, 12 November 2018EgonwReplaced old Uniprot data sources with the new ones.
94684view21:53, 4 October 2017KhanspersModified description
94104view09:28, 21 August 2017DeSlChanged appearence of 2 nodes (changed to text labels, since these cannot be annotated).
94103view09:03, 21 August 2017DeSlChanged layout of legend.
93700view17:20, 10 August 2017AmanzoOntology Term : 'G2/M checkpoint pathway' added !
93699view17:19, 10 August 2017AmanzoOntology Term : 'G1/S DNA damage checkpoint pathway' added !
93698view17:18, 10 August 2017AmanzoOntology Term : 'altered double-strand DNA repair pathway' added !
93697view17:16, 10 August 2017AmanzoOntology Term : 'altered single-strand DNA repair pathway' added !
93696view16:58, 10 August 2017AmanzoOntology Term : 'skin cancer' added !
93695view16:58, 10 August 2017AmanzoOntology Term : 'Seckel syndrome' added !
93694view16:57, 10 August 2017AmanzoOntology Term : 'ATM and Rad3-related (ATR) signaling pathway' added !
93693view16:43, 10 August 2017AmanzoModified description
93692view16:41, 10 August 2017AmanzoModified description
92863view15:31, 10 July 2017AmanzoNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ATMGeneProductENSG00000149311 (Ensembl)
ATRIPProteinQ8WXE1 (Uniprot-TrEMBL)
ATRProteinQ13535 (Uniprot-TrEMBL) From Pathway: SPIKE 00003
BARD1ProteinQ99728 (Uniprot-TrEMBL)
BCL6ProteinP41182 (Uniprot-TrEMBL)
BLMProtein
BRCA1ProteinP38398 (Uniprot-TrEMBL)
BRCA2ProteinP51587 (Uniprot-TrEMBL)
BRCC3ProteinP46736 (Uniprot-TrEMBL)
BRIP1ProteinQ9BX63 (Uniprot-TrEMBL)
CDC25CProteinP30307 (Uniprot-TrEMBL)
CDC45ProteinO75419 (Uniprot-TrEMBL)
CEP164ProteinQ9UPV0 (Uniprot-TrEMBL)
CHK1ProteinO14757 (Uniprot-TrEMBL)
CHK2ProteinO96017 (Uniprot-SwissProt)
CLK2ProteinP49760 (Uniprot-TrEMBL)
CLSPNProteinQ9HAW4 (Uniprot-TrEMBL)
Cdc2ProteinP06493 (Uniprot-TrEMBL)
Cdk2ProteinP24941 (Uniprot-TrEMBL)
Cell Cycle Checkpoint ActivationPathwayWP1775 (WikiPathways)
Cellular response to DNA damagePathway
CycAProteinP14785 (Uniprot-TrEMBL)
CycBProteinP20439 (Uniprot-TrEMBL)
DCLRE1AProteinQ6PJP8 (Uniprot-TrEMBL)
DNA Polymerase delta tetramerProtein
DNA RepairPathwayWP707 (WikiPathways)
Damage ProcessingPathway
E2F1ProteinQ01094 (Uniprot-TrEMBL)
EEF1E1ProteinO43324 (Uniprot-TrEMBL)
EXO1ProteinQ9UQ84 (Uniprot-TrEMBL)
FAM175AProteinQ6UWZ7 (Uniprot-TrEMBL)
FANCAProteinO15360 (Uniprot-TrEMBL)
FANCD2ProteinQ9BXW9 (Uniprot-SwissProt)
FANCD2ProteinQ9BXW9 (Uniprot-TrEMBL)
FANCIProteinQ9NVI1 (Uniprot-TrEMBL)
FEN1ProteinP39748 (Uniprot-TrEMBL)
FOXM1ProteinQ08050 (Uniprot-TrEMBL)
G1/S boundary activationPathway
G2/M-Phase CheckpointPathwayR-HSA-69481 (Reactome)
Gamma H2AXProteinP16104 (Uniprot-TrEMBL)
H2AXProteinP16104 (Uniprot-TrEMBL)
HERC2ProteinO95714 (Uniprot-TrEMBL)
HUS1ProteinO60921 (Uniprot-TrEMBL)
IKPKBProteinQ9Y6K9 (Uniprot-TrEMBL)
M-Phase ProgressionPathwayhsa04110 (KEGG Pathway)
MCM2ProteinP49736 (Uniprot-TrEMBL)
MCPH1ProteinQ8NEM0 (Uniprot-TrEMBL)
MDC1ProteinQ14676 (Uniprot-TrEMBL)
MDM2ProteinQ00987 (Uniprot-TrEMBL)
MRE11AProteinP49959 (Uniprot-TrEMBL)
MSH2ProteinP43246 (Uniprot-TrEMBL)
MUTL-ALPHA MLH1ProteinP40692 (Uniprot-TrEMBL)
NBNProteinO60934 (Uniprot-TrEMBL)
PALB2ProteinQ86YC2 (Uniprot-TrEMBL)
PARP1ProteinP09874 (Uniprot-TrEMBL)
PCNAProteinP12004 (Uniprot-TrEMBL)
PLK1ProteinP53350 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
POLBProteinP06746 (Uniprot-TrEMBL)
POLNProteinQ7Z5Q5 (Uniprot-TrEMBL)
PPM1DProteinO15297 (Uniprot-TrEMBL)
PRKDCProteinP78527 (Uniprot-TrEMBL)
RAD17ProteinO75943 (Uniprot-TrEMBL)
RAD1ProteinO60671 (Uniprot-TrEMBL)
RAD50ProteinQ92878 (Uniprot-TrEMBL)
RAD51ProteinQ06609 (Uniprot-TrEMBL)
RAD52ProteinP43351 (Uniprot-TrEMBL)
RAD9ProteinQ99638 (Uniprot-TrEMBL)
RBBP8ProteinQ99708 (Uniprot-TrEMBL)
RECQL4ProteinO94761 (Uniprot-TrEMBL)
RECQL5ProteinO94762 (Uniprot-TrEMBL)
RECQLProteinP46063 (Uniprot-TrEMBL)
RFWD3ProteinQ6PCD5 (Uniprot-TrEMBL)
RMI1ProteinQ9H9A7 (Uniprot-TrEMBL)
RNF8Protein
RPA1Protein
RPA1ProteinP27694 (Uniprot-TrEMBL)
RPA2ProteinP15927 (Uniprot-TrEMBL)
RecQ-like helicases
SHFM1ProteinP60896 (Uniprot-TrEMBL)
SMARCAL1ProteinQ9NZC9 (Uniprot-TrEMBL)
SMARCC2ProteinQ8TAQ2 (Uniprot-TrEMBL)
SMC1AProteinQ14683 (Uniprot-TrEMBL)
SP1ProteinP08047 (Uniprot-TrEMBL)
TDP1ProteinQ9NUW8 (Uniprot-TrEMBL)
TOP3AProteinQ13472 (Uniprot-TrEMBL)
TOPBP1ProteinQ92547 (Uniprot-TrEMBL)
TP53BP1ProteinQ12888 (Uniprot-TrEMBL)
TP53ProteinP04637 (Uniprot-TrEMBL)
TRIM28ProteinQ13263 (Uniprot-TrEMBL)
The intra-S-phase

checkpoint mediated arrest of cell cycle

progression
PathwayR-HSA-5693571 (Reactome)
UB2D3ProteinP61077 (Uniprot-TrEMBL)
UIMC1ProteinQ96RL1 (Uniprot-TrEMBL)
UPF1ProteinQ92900 (Uniprot-TrEMBL)
USP1ProteinO94782 (Uniprot-TrEMBL)
WRNProteinQ14191 (Uniprot-TrEMBL)
XPAProteinP23025 (Uniprot-TrEMBL)
XRCC5ProteinP13010 (Uniprot-TrEMBL)
ssDNA

Annotated Interactions

SourceTargetTypeDatabase referenceComment
ATMTP53mim-stimulation00006 (SPIKE)
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