DNA IR-damage and cellular response via ATR (WP4016)

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 ATR-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.
last edited

Authors

Amanzo, DeSl, Khanspers, Egonw, Fehrhart, Finterly, and Eweitz

Cited In

Organism

Homo sapiens

Communities

CPTAC

Annotations

Disease Ontology: skin cancer Seckel syndrome cancer

Pathway Ontology: altered single-strand DNA repair pathway ATM and Rad3-related (ATR) signaling pathway G2/M checkpoint pathway altered double-strand DNA repair pathway G1/S DNA damage checkpoint pathway

Participants

Label Type Compact Identifier
ATR Protein uniprot:Q13535
RPA2 Protein uniprot:P15927
RBBP8 Protein uniprot:Q99708
MCPH1 Protein uniprot:Q8NEM0
RFWD3 Protein uniprot:Q6PCD5
RAD51 Protein uniprot:Q06609
E2F1 Protein uniprot:Q01094
FANCI Protein uniprot:Q9NVI1
MSH2 Protein uniprot:P43246
TP53BP1 Protein uniprot:Q12888
PPM1D Protein uniprot:O15297
PRKDC Protein uniprot:P78527
MRE11A Protein uniprot:P49959
PCNA Protein uniprot:P12004
MDC1 Protein uniprot:Q14676
CHK1 Protein uniprot:O14757
FANCA Protein uniprot:O15360
TP53 Protein uniprot:P04637
UB2D3 Protein uniprot:P61077
M-phase progression Pathway kegg.pathway:hsa04110
USP1 Protein uniprot:O94782
CLSPN Protein uniprot:Q9HAW4
SMARCAL1 Protein uniprot:Q9NZC9
MDM2 Protein uniprot:Q00987
SMC1A Protein uniprot:Q14683
SMARCC2 Protein uniprot:Q8TAQ2
Intra-S-phasecheckpoint mediatedarrest of cell cycleprogression Pathway reactome:R-HSA-5693571
XPA Protein uniprot:P23025
BLM Protein None
UPF1 Protein uniprot:Q92900
RAD50 Protein uniprot:Q92878
NBN Protein uniprot:O60934
POLN Protein uniprot:Q7Z5Q5
MCPH1 Protein uniprot:Q8NEM0
MCM2 Protein uniprot:P49736
HERC2 Protein uniprot:O95714
RAD52 Protein uniprot:P43351
RAD17 Protein uniprot:O75943
CEP164 Protein uniprot:Q9UPV0
BCL6 Protein uniprot:P41182
CHK2 Protein uniprot:O96017
XRCC5 Protein uniprot:P13010
SP1 Protein uniprot:P08047
POLB Protein uniprot:P06746
BRCA2 Protein uniprot:P51587
EXO1 Protein uniprot:Q9UQ84
EEF1E1 Protein uniprot:O43324
TDP1 Protein uniprot:Q9NUW8
TRIM28 Protein uniprot:Q13263
RAD9 Protein uniprot:Q99638
PLK1 Protein uniprot:P53350
MUTL-ALPHAMLH1 Protein uniprot:P40692
BRCA1 Protein uniprot:P38398
DCLRE1A Protein uniprot:Q6PJP8
IKPKB Protein uniprot:Q9Y6K9
CLK2 Protein uniprot:P49760
ATM GeneProduct ensembl:ENSG00000149311
H2AX Protein uniprot:P16104
DNA repair Pathway wikipathways:WP707
RNF8 Protein None
Cell cyclecheckpoint activation Pathway wikipathways:WP1775
G2/M-phase checkpoint Pathway reactome:R-HSA-69481
Damage processing Pathway None
DNA Polymerasedelta tetramer Protein None
CDC25C Protein uniprot:P30307
MRE11A Protein uniprot:P49959
RAD50 Protein uniprot:Q92878
NBN Protein uniprot:O60934
GammaH2AX Protein uniprot:P16104
MDC1 Protein uniprot:Q14676
FANCD2 Protein uniprot:Q9BXW9
FANCD2 Protein uniprot:Q9BXW9
BRCA2 Protein uniprot:P51587
UIMC1 Protein uniprot:Q96RL1
TOPBP1 Protein uniprot:Q92547
PML Protein uniprot:P29590
RPA1 Protein uniprot:P27694
BRIP1 Protein uniprot:Q9BX63
RAD1 Protein uniprot:O60671
HUS1 Protein uniprot:O60921
BARD1 Protein uniprot:Q99728
BRCC3 Protein uniprot:P46736
FAM175A Protein uniprot:Q6UWZ7
CDC45 Protein uniprot:O75419
RECQL5 Protein uniprot:O94762
WRN Protein uniprot:Q14191
RECQL4 Protein uniprot:O94761
RECQL Protein uniprot:P46063
RMI1 Protein uniprot:Q9H9A7
TOP3A Protein uniprot:Q13472
PARP1 Protein uniprot:P09874
RPA1 Protein None
ATRIP Protein uniprot:Q8WXE1
RAD9 Protein uniprot:Q99638
RAD1 Protein uniprot:O60671
HUS1 Protein uniprot:O60921
SHFM1 Protein uniprot:P60896
FOXM1 Protein uniprot:Q08050
PALB2 Protein uniprot:Q86YC2
CycA Protein uniprot:P14785
Cdk2 Protein uniprot:P24941
CycB Protein uniprot:P20439
Cdc2 Protein uniprot:P06493
G1/S boundary activation Pathway None
FEN1 Protein uniprot:P39748
BARD1 Protein uniprot:Q99728
UIMC1 Protein uniprot:Q96RL1
BRCA1 Protein uniprot:P38398
RBBP8 Protein uniprot:Q99708
BLM Protein None
RMI1 Protein uniprot:Q9H9A7
TOP3A Protein uniprot:Q13472
CycA Protein uniprot:P14785
Cdk2 Protein uniprot:P24941
CycB Protein uniprot:P20439
Cdc2 Protein uniprot:P06493
ATR Protein uniprot:Q13535
ATRIP Protein uniprot:Q8WXE1
Cellular responseto DNA damage Pathway None

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