miRNA regulation of DNA damage response (WP1530)

This is the first of two pathways which deals with the DNA damage response. It comprises two central gene products (ATM and ATR) influenced by different sources of DNA damage (in blue). The two central genes can both be divides into their most important genes. For the ATM pathway these are TP53 and CHEK2, while CHEK1 is most important for the ATR pathway. The goal of this first pathway is to provide an overview of the most important gene products, processes and changes in cell condition elicited by the DNA damage response while keeping it clear and understandable. Also some microRNAs are implemented to visualize the possible effects they can induce. By doing so a better understanding of the role microRNA play in the DNA damage response might arise. All processes take place in the cytoplasm, except when mentioned differently. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1530 CPTAC Assay Portal].
last edited


J.krumeich, Stan.gaj, Mkutmon, Andra, MaintBot, MartijnVanIersel, Khanspers, Egonw, AlexanderPico, Zari, Ryanmiller, Susan, Finterly, and Eweitz

Cited In


Homo sapiens



Pathway Ontology: microRNA pathway DNA repair pathway


Label Type Compact Identifier
Alkylating agents Metabolite chebi:22333
MIR29B1 Rna ensembl:ENSG00000283797
RAD51 GeneProduct ensembl:ENSG00000051180
APAF1 GeneProduct ensembl:ENSG00000120868
CCNB2 GeneProduct ensembl:ENSG00000157456
RAD52 GeneProduct ensembl:ENSG00000002016
RB1 GeneProduct ensembl:ENSG00000139687
GADD45B GeneProduct ensembl:ENSG00000099860
CDKN1A GeneProduct ensembl:ENSG00000124762
Estradiol Metabolite chebi:16469
ABL1 GeneProduct ensembl:ENSG00000097007
ATR GeneProduct ensembl:ENSG00000175054
MIR223 Rna ensembl:ENSG00000284567
hsa-mir-222 Rna ensembl:ENSG00000207725
CDK2 GeneProduct ensembl:ENSG00000123374
CCND3 GeneProduct ensembl:ENSG00000112576
GADD45A GeneProduct ensembl:ENSG00000116717
CDKN1B GeneProduct ensembl:ENSG00000111276
RAD17 GeneProduct ensembl:ENSG00000152942
RFC GeneProduct ncbigene:5981
CHEK1 GeneProduct ensembl:ENSG00000149554
PIDD GeneProduct ncbigene:55367
TP53AIP1 GeneProduct ensembl:ENSG00000120471
CCND1 GeneProduct ensembl:ENSG00000110092
BID GeneProduct ensembl:ENSG00000015475
CASP9 GeneProduct ensembl:ENSG00000132906
GADD45G GeneProduct ensembl:ENSG00000130222
hsa-mir-21 Rna ensembl:ENSG00000284190
MIR29A Rna ensembl:ENSG00000284032
CCND2 GeneProduct ensembl:ENSG00000118971
PML GeneProduct ensembl:ENSG00000140464
MIR15a/16-1 Rna None
MIR424 Rna ensembl:ENSG00000284231
NBN GeneProduct ncbigene:4683
CHEK2 GeneProduct ensembl:ENSG00000183765
FANCD2 GeneProduct ensembl:ENSG00000144554
CDK5 GeneProduct ensembl:ENSG00000164885
hsa-mir-449a Rna ensembl:ENSG00000198983
TLK2 GeneProduct ensembl:ENSG00000146872
hsa-mir-122 Rna ensembl:ENSG00000207778
TLK1 GeneProduct ensembl:ENSG00000198586
GADD45G GeneProduct ensembl:ENSG00000130222
hsa-mir-373 Rna ensembl:ENSG00000199143
SFN GeneProduct ensembl:ENSG00000175793
MIR15A GeneProduct ensembl:ENSG00000283785
BRCA1 GeneProduct ensembl:ENSG00000012048
GADD45B GeneProduct ensembl:ENSG00000099860
DDB2 GeneProduct ensembl:ENSG00000134574
PMAIP1 GeneProduct ensembl:ENSG00000141682
RB1 GeneProduct ensembl:ENSG00000139687
RPA2 GeneProduct ensembl:ENSG00000117748
MIR17 Rna ensembl:ENSG00000284536
GADD45A GeneProduct ensembl:ENSG00000116717
MDM2 GeneProduct ensembl:ENSG00000135679
FAS GeneProduct ensembl:ENSG00000026103
hsa-mir-16 Rna ensembl:ENSG00000208006
hsa-let-7a-1/7d Rna None
hsa-mir-181a Rna ensembl:ENSG00000207759
CCNE2 GeneProduct ensembl:ENSG00000175305
MIR17/92a-1 Rna ensembl:ENSG00000215417
Caffeine Metabolite chemspider:2424
RAD1 GeneProduct ensembl:ENSG00000113456
hsa-mir-143/145 Rna None
MIR330 Rna ensembl:ENSG00000284544
hsa-mir-221 Rna ensembl:ENSG00000207870
PRKDC GeneProduct ensembl:ENSG00000253729
CASP8 GeneProduct ensembl:ENSG00000064012
CCNG1 GeneProduct ensembl:ENSG00000113328
Apoptosis Pathway wikipathways:WP254
BAX GeneProduct ensembl:ENSG00000087088
CASP3 GeneProduct ensembl:ENSG00000164305
CDK6 GeneProduct ensembl:ENSG00000105810
Cell Cycle Pathway wikipathways:WP179
ATM GeneProduct ensembl:ENSG00000149311
hsa-mir-16 Rna ensembl:ENSG00000208006
SESN1 GeneProduct ensembl:ENSG00000080546
E2F1 GeneProduct ensembl:ENSG00000101412
CDK4 GeneProduct ensembl:ENSG00000135446
SMC1A GeneProduct ensembl:ENSG00000072501
CYCS GeneProduct ensembl:ENSG00000172115
MIR20A GeneProduct ensembl:ENSG00000283762
TP53 GeneProduct ensembl:ENSG00000141510
hsa-mir-16 Rna ensembl:ENSG00000208006
Senescence Pathway wikipathways:WP615
MIR145 GeneProduct ensembl:ENSG00000276365
MIR17 Rna ensembl:ENSG00000284536
HUS1 GeneProduct ensembl:ENSG00000188996
miR-143/145 polycistron Rna None
hsa-mir-449b Rna ensembl:ENSG00000207728
CCNE1 GeneProduct ensembl:ENSG00000105173
CCNB3 GeneProduct ensembl:ENSG00000147082
BBC3 GeneProduct ensembl:ENSG00000105327
RAD50 GeneProduct ensembl:ENSG00000113522
c-Myc GeneProduct ncbigene:4609
MIR195/497 Rna None
hsa-miR-106b/25 Rna ncbigene:4176
E2F1 GeneProduct ensembl:ENSG00000101412
7-hydroxystaurosporine Metabolite chemspider:65225
MIR29b-1/29a Rna None
RRM2B GeneProduct ensembl:ENSG00000048392
hsa-mir-210 Rna ensembl:ENSG00000199038
hsa-mir-421 Rna ensembl:ENSG00000202566
hsa-mir-449a Rna ensembl:ENSG00000198983
MIR195 Rna ensembl:ENSG00000284112
CDK1 GeneProduct ensembl:ENSG00000170312
hsa-miR-449c/449a Rna ncbigene:166979
CREB1 GeneProduct ncbigene:1385
MRE11 GeneProduct ncbigene:4361
hsa-mir-34b/34c Rna None
CDC25C GeneProduct ensembl:ENSG00000158402
ATRIP GeneProduct ncbigene:84126
RAD9A GeneProduct ensembl:ENSG00000172613
TNFRSF10B GeneProduct ensembl:ENSG00000120889
hsa-mir-15b/16-2 Rna None
hsa-mir-15b/16-2 Rna None
H2AFX GeneProduct ensembl:ENSG00000188486
hsa-mir-34b Rna ensembl:ENSG00000207811
hsa-mir-24-1 GeneProduct ensembl:ENSG00000284459
CCNB1 GeneProduct ensembl:ENSG00000134057
hsa-mir-203 Rna ensembl:ENSG00000207568
MIR29c Rna ensembl:ENSG00000284214
hsa-mir-106b Rna ensembl:ENSG00000208036
CDC25A GeneProduct ensembl:ENSG00000164045


  1. Cory S, Huang DCS, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003 Nov 24;22(53):8590–607. PubMed Europe PMC Scholia
  2. Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, Elowitz MB, et al. Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat Genet. 2004 Feb;36(2):147–50. PubMed Europe PMC Scholia
  3. Zhou B-BS, Bartek J. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer. 2004 Mar;4(3):216–25. PubMed Europe PMC Scholia
  4. Ohtsuka T, Jensen MR, Kim HG, Kim K-T, Lee SW. The negative role of cyclin G in ATM-dependent p53 activation. Oncogene. 2004 Jul 8;23(31):5405–8. PubMed Europe PMC Scholia
  5. Pagano M, Jackson PK. Wagging the dogma; tissue-specific cell cycle control in the mouse embryo. Cell. 2004 Sep 3;118(5):535–8. PubMed Europe PMC Scholia
  6. Ljungman M, Lane DP. Transcription - guarding the genome by sensing DNA damage. Nat Rev Cancer. 2004 Sep;4(9):727–37. PubMed Europe PMC Scholia
  7. Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev. 2004 Nov 15;18(22):2699–711. PubMed Europe PMC Scholia
  8. Reshmi SC, Gollin SM. Chromosomal instability in oral cancer cells. J Dent Res. 2005 Feb;84(2):107–17. PubMed Europe PMC Scholia
  9. Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005 Jan;6(1):44–55. PubMed Europe PMC Scholia
  10. Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol. 2005 Mar;5(3):189–200. PubMed Europe PMC Scholia
  11. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005 Jun 9;435(7043):839–43. PubMed Europe PMC Scholia
  12. Harrison JC, Haber JE. Surviving the breakup: the DNA damage checkpoint. Annu Rev Genet. 2006;40:209–35. PubMed Europe PMC Scholia
  13. Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006 Sep;7(9):667–77. PubMed Europe PMC Scholia
  14. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006 Nov;6(11):846–56. PubMed Europe PMC Scholia
  15. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006 Dec;6(12):909–23. PubMed Europe PMC Scholia
  16. Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F, et al. An E2F/miR-20a autoregulatory feedback loop. J Biol Chem. 2007 Jan 26;282(4):2135–43. PubMed Europe PMC Scholia
  17. Woods K, Thomson JM, Hammond SM. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J Biol Chem. 2007 Jan 26;282(4):2130–4. PubMed Europe PMC Scholia
  18. Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007 Apr;8(4):275–83. PubMed Europe PMC Scholia
  19. Boutros R, Lobjois V, Ducommun B. CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer. 2007 Jul;7(7):495–507. PubMed Europe PMC Scholia
  20. Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA, et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 2007 Aug 10;282(32):23716–24. PubMed Europe PMC Scholia
  21. Wang W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007 Oct;8(10):735–48. PubMed Europe PMC Scholia
  22. Löbrich M, Jeggo PA. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer. 2007 Nov;7(11):861–9. PubMed Europe PMC Scholia
  23. Antoni L, Sodha N, Collins I, Garrett MD. CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat Rev Cancer. 2007 Dec;7(12):925–36. PubMed Europe PMC Scholia
  24. Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, et al. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol. 2008 Apr;28(7):2167–74. PubMed Europe PMC Scholia
  25. Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008 Sep 25;27(43):5651–61. PubMed Europe PMC Scholia
  26. Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008 Jun;13(6):496–506. PubMed Europe PMC Scholia
  27. Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J, et al. miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Nucleic Acids Res. 2008 Sep;36(16):5391–404. PubMed Europe PMC Scholia
  28. Lee S-O, Masyuk T, Splinter P, Banales JM, Masyuk A, Stroope A, et al. MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest. 2008 Nov;118(11):3714–24. PubMed Europe PMC Scholia
  29. Brosh R, Shalgi R, Liran A, Landan G, Korotayev K, Nguyen GH, et al. p53-Repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation. Mol Syst Biol. 2008;4:229. PubMed Europe PMC Scholia
  30. Chargari C, Toillon RA, Macdermed D, Castadot P, Magné N. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Lancet Oncol. 2009 Jan;10(1):53–60. PubMed Europe PMC Scholia
  31. Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, et al. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med. 2008 Dec;12(6A):2189–204. PubMed Europe PMC Scholia
  32. Crosby ME, Kulshreshtha R, Ivan M, Glazer PM. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 2009 Feb 1;69(3):1221–9. PubMed Europe PMC Scholia
  33. Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, et al. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3207–12. PubMed Europe PMC Scholia
  34. Pigazzi M, Manara E, Baron E, Basso G. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Cancer Res. 2009 Mar 15;69(6):2471–8. PubMed Europe PMC Scholia
  35. Cuesta R, Martínez-Sánchez A, Gebauer F. miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells. Mol Cell Biol. 2009 May;29(10):2841–51. PubMed Europe PMC Scholia
  36. Lal A, Pan Y, Navarro F, Dykxhoorn DM, Moreau L, Meire E, et al. miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. Nat Struct Mol Biol. 2009 May;16(5):492–8. PubMed Europe PMC Scholia
  37. Pothof J, Verkaik NS, van IJcken W, Wiemer EAC, Ta VTB, van der Horst GTJ, et al. MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. EMBO J. 2009 Jul 22;28(14):2090–9. PubMed Europe PMC Scholia
  38. Lee K-H, Chen Y-L, Yeh S-D, Hsiao M, Lin J-T, Goan Y-G, et al. MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. Oncogene. 2009 Sep 24;28(38):3360–70. PubMed Europe PMC Scholia
  39. Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko RJ Jr, et al. microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res. 2009 Oct 15;69(20):8157–65. PubMed Europe PMC Scholia
  40. Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M, et al. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes Dev. 2009 Oct 15;23(20):2388–93. PubMed Europe PMC Scholia
  41. Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK, et al. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Blood. 2010 Mar 4;115(9):1768–78. PubMed Europe PMC Scholia
  42. Hu H, Du L, Nagabayashi G, Seeger RC, Gatti RA. ATM is down-regulated by N-Myc-regulated microRNA-421. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1506–11. PubMed Europe PMC Scholia
  43. Zhao J-J, Lin J, Lwin T, Yang H, Guo J, Kong W, et al. microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood. 2010 Apr 1;115(13):2630–9. PubMed Europe PMC Scholia
  44. Wong P, Iwasaki M, Somervaille TCP, Ficara F, Carico C, Arnold C, et al. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Cancer Res. 2010 May 1;70(9):3833–42. PubMed Europe PMC Scholia