DNA damage response (DDR)



After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
p53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA damage.[33] At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21 mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.

The DNA damage response and cancer
The DDR is highly relevant to all aspects of cancer.
First, numerous cancer predisposing syndromes are attributed to mutations in genes in the DDR pathways such as TP53 (Tumour suppressor P53, mutated in Li Fraumeni syndrome and mutated in more than 50% of all sporadic cancers), ATM (mutated in Ataxia-Telangiectasia), BRCA1/2 (mutated in 50% of familial breast and ovarian cancer patients), XP-A to -G and XP-V (defective in Xeroderma Pigmentosum (XP)), numerous FANC genes (deficient in patients with Fanconi's Anaemia), etc.
Second, DDR is important for the onset of carcinogenesis and thereby also for prevention, since most carcinogens are genotoxic, targeting the DNA in a direct or indirect manner.
Third, DDR impinges on the evolution to a malignant tumorigenic state, which is driven by mutations and chromosomal instability. The latter can lead to inactivation of tumour suppressor genes, activation of proto-oncogenes and bypassing telomere attrition.
Fourth, DDR mechanisms are also relevant to the effectiveness of classical therapeutic treatments, such as radio- and chemotherapy, because these therapies are strongly based on DNA damage induction, which triggers cell death particularly in proliferating cells.
Fifth, the DDR also affects therapy resistance, due to attained genetic or epigenetic alterations that prevent cell death (e.g. by apoptosis), which undermines effective cure in most cancer treatments.
Finally, hyper- and hyposensitivity of the normal tissue of patients to these classical anti-cancer modalities may at least in part be caused by inter-individual differences in repair and response systems. Thus, the DDR is central to the cancer problem. Due to the intimate links between DDR and carcinogenesis, most tumours have acquired one or more compromised aspects of the DDR in order to reach the number of oncogenic changes required for malignancy and/or to avert cell death despite ongoing DNA-damage induction. Therefore, assessment of the DDR status in tumours is very valuable not only for prevention, diagnosis and prediction of individual cancer susceptibility, but also for predicting individual response to treatment and for counteracting side effects, including long-term consequences and development of therapy resistance.


DNA checkpoint control
DNA damage checkpoint
checkpoint control


ORTHOLOGY CLASS Homo sapiens L. (human) [HSA] Mus musculus L. (mouse) [MMU] Caenorhabditis elegans Maupas (nematode) [CEL] Drosophila melanogaster Meigen (fruit fly) [DME] Saccharomyces cerevisiae Meyen ex E.C. Hansen (budding yeast) [SCE] Schizo-saccharomyces pombe Lindner (fission yeast) [SPO] Escherichia coli Migula (bacterium) K-12 MG1655 [ECO] Arabidopsis thaliana (L.) Heynh. (mouse-ear cress) [ATH]
ko:K10998 (replication fork protection complex subunit Csm3/Swi3) CSM3 swi3
ko:K10997 (replication fork protection complex subunit Tof1/Swi1) TOF1 swi1
ko:K10904 (TIMELESS-interacting protein) TIPIN Tipin tipin tipin
ko:K03155 (timeless) TIMELESS Timeless tim-1 timeout ATIM
ko:K06663 (DNA damage checkpoint protein) DDC1
ko:K02544 (G2-specific checkpoint protein) MEC3
ko:K10996 (checkpoint protein HUS1B) HUS1B Hus1b
ko:K10903 (HUS1 checkpoint protein) HUS1 Hus1 hus-1 Hus1-like hus1 AtHus1
ko:K10995 (cell cycle checkpoint control protein RAD9B) RAD9B Rad9b
ko:K10994 (cell cycle checkpoint control protein RAD9A [EC:]) RAD9A Rad9 hpr-9 Rad9 rad9 RAD9
ko:K02830 (cell cycle checkpoint protein [EC:]) RAD1 Rad1 mrt-2 Rad1 RAD17 rad1 AtRad1
ko:K06662 (cell cycle checkpoint protein) RAD17 Rad17 hpr-17 Rad17 RAD24 rad17 AtRAD17
ko:K15081 (antagonist of mitotic exit network protein 1) AMN1
ko:K02543 (cell cycle checkpoint protein MEC1) MEC1
ko:K06661 (DNA repair protein RAD9) RAD9
ko:K02633 (period circadian protein) PER2
ko:K02831 (ser/thr/tyr protein kinase RAD53 [EC:2.7.11.-]) RAD53 cds1
ko:K06641 (serine/threonine-protein kinase Chk2 [EC:]) CHEK2 (CHK2) Chek2 chk-2 lok DUN1
ko:K02216 (serine/threonine-protein kinase Chk1 [EC:]) CHEK1 (CHK1) Chek1 chk-1 grp CHK1 chk1
ko:K04451 (tumor protein p53) TP53 Trp53
ko:K04728 (ataxia telangectasia mutated family protein [EC:]) ATM Atm atm-1 tefu TEL1 tel1 ATM
ko:K10905 (ATR interacting protein) ATRIP Atrip
ko:K06640 (serine/threonine-protein kinase ATR [EC:]) ATR Atr mei-41 rad3 ATRAD3


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Last modification date: Oct. 18, 2011