TP53 Regulates Transcription of DNA Repair Genes

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Several DNA repair genes contain p53 response elements and their transcription is positively regulated by TP53 (p53). TP53-mediated regulation probably ensures increased protein level of DNA repair genes under genotoxic stress.

TP53 directly stimulates transcription of several genes involved in DNA mismatch repair, including MSH2 (Scherer et al. 2000, Warnick et al. 2001), PMS2 and MLH1 (Chen and Sadowski 2005). TP53 also directly stimulates transcription of DDB2, involved in nucleotide excision repair (Tan and Chu 2002), and FANCC, involved in the Fanconi anemia pathway that repairs DNA interstrand crosslinks (Liebetrau et al. 1997). Other p53 targets that can influence DNA repair functions are RRM2B (Kuo et al. 2012), XPC (Fitch et al. 2003), GADD45A (Amundson et al. 2002), CDKN1A (Cazzalini et al. 2010) and PCNA (Xu and Morris 1999). Interestingly, the responsiveness of some of these DNA repair genes to p53 activation has been shown in human cells but not for orthologous mouse genes (Jegga et al. 2008, Tan and Chu 2002). Contrary to the positive modulation of nucleotide excision repair (NER) and mismatch repair (MMR), p53 can negatively modulate base excision repair (BER), by down-regulating the endonuclease APEX1 (APE1), acting in concert with SP1 (Poletto et al. 2016).

Expression of several DNA repair genes is under indirect TP53 control, through TP53-mediated stimulation of cyclin K (CCNK) expression (Mori et al. 2002). CCNK is the activating cyclin for CDK12 and CDK13 (Blazek et al. 2013). The complex of CCNK and CDK12 binds and phosphorylates the C-terminal domain of the RNA polymerase II subunit POLR2A, which is necessary for efficient transcription of long DNA repair genes, including BRCA1, ATR, FANCD2, FANCI, ATM, MDC1, CHEK1 and RAD51D. Genes whose transcription is regulated by the complex of CCNK and CDK12 are mainly involved in the repair of DNA double strand breaks and/or the Fanconi anemia pathway (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015, Ekumi et al. 2015).

Literature References
PubMed ID Title Journal Year
15781865 Identification of the mismatch repair genes PMS2 and MLH1 as p53 target genes by using serial analysis of binding elements

Sadowski, I, Chen, J

Proc. Natl. Acad. Sci. U.S.A. 2005
9858527 p53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation

Morris, GF, Xu, J

Mol. Cell. Biol. 1999
22012619 The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

Cimermancic, P, Johansen, E, Ule, J, Peterlin, BM, Hulinkova, P, Luo, Z, Blazek, D, Kohoutek, J, Bartholomeeusen, K

Genes Dev. 2011
26773055 p53 coordinates base excision repair to prevent genomic instability

Fletcher, SC, Legrand, AJ, Dianov, GL, Poletto, M

Nucleic Acids Res. 2016
11350971 Identification of a p53 response element in the promoter region of the hMSH2 gene required for expression in A2780 ovarian cancer cells

Dabbas, B, Strait, KA, Ford, CD, Warnick, CT

J. Biol. Chem. 2001
11988847 Cyclin K as a direct transcriptional target of the p53 tumor suppressor

Arakawa, H, Nakamura, Y, Anazawa, Y, Mori, T, Matsui, K, Fukuda, S

Neoplasia 2002
25429106 Expression, purification, and identification of associated proteins of the full-length hCDK12/CyclinK complex

Bartkowiak, B, Greenleaf, AL

J. Biol. Chem. 2015
12771027 p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation-induced DNA damage, in vivo

Ford, JM, Cross, IV, Fitch, ME

Carcinogenesis 2003
10984493 p53 and c-Jun functionally synergize in the regulation of the DNA repair gene hMSH2 in response to UV

Maier, SM, Seifert, M, Angel, P, Scherer, SJ, Zang, KD, Müller-Hermelink, HK, Hanselmann, RG, Welter, C, Schartl, M

J. Biol. Chem. 2000
20096807 Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response

Stivala, LA, Prosperi, E, Scovassi, AI, Savio, M, Cazzalini, O

Mutat. Res. 2010
22988298 Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II

Kuzyk, MA, Vollett, SE, Tien, JF, Ichu, TA, Cheng, SW, Chang, VC, Marra, MA, Griffith, M, Moradian, A, Morin, GB

Mol. Cell. Biol. 2012
18187580 Functional evolution of the p53 regulatory network through its target response elements

Menendez, D, Inga, A, Jegga, AG, Aronow, BJ, Resnick, MA

Proc. Natl. Acad. Sci. U.S.A. 2008
12170774 A nucleotide excision repair master-switch: p53 regulated coordinate induction of global genomic repair genes

Amundson, SA, Do, KT, Fornace, AJ, Patterson, A

Cancer Biol. Ther. 2002
24662513 The structure and substrate specificity of human Cdk12/Cyclin K

Merzel Schachter, M, Geyer, M, Eick, D, Vogel-Bachmayr, K, Blazek, D, Farnung, L, Anand, K, Bösken, CA, Fisher, RP, Hintermair, C

Nat Commun 2014
23139867 RRM2B suppresses activation of the oxidative stress pathway and is up-regulated by p53 during senescence

Yen, Y, Chi, M, Lee, MT, Xue, L, Chang, L, Sy, AJ, Chiang, MI, Yen, T, Chu, P, Kuo, ML

Sci Rep 2012
9063748 p53 activates Fanconi anemia group C gene expression

Grummt, F, Hoehn, H, Savoia, A, Liebetrau, W, Budde, A

Hum. Mol. Genet. 1997
11971958 p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice

Tan, T, Chu, G

Mol. Cell. Biol. 2002
25712099 Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex

Ekumi, KM, Paculova, H, Barboric, M, Bryja, V, Geyer, M, Rybarikova, J, Blazek, D, Pospichalova, V, Lenasi, T, Bösken, CA

Nucleic Acids Res. 2015
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