DNA IR-double strand breaks and cellular response via ATM (WP3959)

Homo sapiens

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.

Authors

Arturo Manzo-Fontes P D , Kristina Hanspers , Egon Willighagen , Eric Weitz , and Marvin Martens

Activity

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Organisms

Homo sapiens

Communities

CPTAC

Annotations

Disease Ontology

disease of cellular proliferation

Pathway Ontology

altered programmed cell death pathway altered double-strand DNA repair pathway pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis

Participants

Label Type Compact URI Comment
ATM GeneProduct ensembl:ENSG00000149311
RAD9A GeneProduct ensembl:ENSG00000172613
ATF2 GeneProduct ensembl:ENSG00000115966
ATR Protein uniprot:Q13535 From Pathway: SPIKE 00003
MCPH1 Protein uniprot:Q8NEM0
p73 Protein uniprot:O15350
RAD51 Protein uniprot:Q06609
BAX Protein uniprot:Q07812
ATM Protein uniprot:Q13315
E2F1 Protein uniprot:Q01094
EXO1 Protein uniprot:Q9UQ84
KAT5 Protein uniprot:Q92993 Q92993 is the catalytic subunit of the NuA4 histone acetyltransferase complex.
TP53BP1 Protein uniprot:Q12888
STK3 Protein uniprot:Q13188
RASSF1 Protein uniprot:Q9NS23
SMC3 Protein uniprot:Q9UQE7
DNA-PK Protein uniprot:P78527
MRE11A Protein uniprot:P49959
PCNA Protein uniprot:P12004
HSF1 Protein uniprot:Q00613
MDC1 Protein uniprot:Q14676
ACTL6A Protein uniprot:O96019
CHK1 Protein uniprot:O14757
APAF1 Protein uniprot:O14727
TP53 Protein uniprot:P04637
DCLRE1C Protein uniprot:Q96SD1
TRAF6 Protein uniprot:Q9Y4K3
TERF2 Protein uniprot:Q15554
UPF1 Protein uniprot:Q92900
CASP9 Protein uniprot:P55211
CDK5 Protein uniprot:Q00535
MDM2 Protein uniprot:Q00987
BLM Protein uniprot:P54132
RAD50 Protein uniprot:Q92878
NBN Protein uniprot:O60934
MCPH1 Protein uniprot:Q8NEM0
RAD52 Protein uniprot:P43351
OBFC2B Protein uniprot:Q9BQ15
RAD17 Protein uniprot:O75943
BAK1 Protein uniprot:Q16611
PARP1 Protein uniprot:P09874
BRCA2 Protein uniprot:P51587
CHK2 Protein uniprot:O96017
TRIM28 Protein uniprot:Q13263
SMC1A Protein uniprot:Q14683
LATS1 Protein uniprot:O95835
BRCA1 Protein uniprot:P38398
ARF(CDKN2A) Protein uniprot:Q8N726
BID Protein uniprot:P55957
H2AX Protein uniprot:P16104
APAF1 Protein uniprot:O14727
CASP9 Protein uniprot:P55211
CASP3 Protein uniprot:P42574
RNF8 Protein uniprot:O76064
RIF1 Protein uniprot:Q5UIP0
DNA Polymerasedelta tetramer Protein uniprot:P30261
CDC25C Protein uniprot:P30307
ATM Protein uniprot:Q13315
TRAF6 Protein uniprot:Q9Y4K3
ABL1 Protein uniprot:P00519
ACTL6A Protein uniprot:O96019
KAT5 Protein uniprot:Q92993 Q92993 is the catalytic subunit of the NuA4 histone acetyltransferase complex.
MDM2 Protein uniprot:Q00987
ARF(CDKN2A) Protein uniprot:Q8N726
MRE11A Protein uniprot:P49959
RAD50 Protein uniprot:Q92878
NBN Protein uniprot:O60934
GammaH2AX Protein uniprot:P16104
MDC1 Protein uniprot:Q14676
YAP1 Protein uniprot:P46937
FANCD2 Protein uniprot:Q9BXW9
FANCD1 Protein uniprot:P51587
FANCD1 Protein uniprot:P51587
BRCA2 Protein uniprot:P51587

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