Biotechnology Letters

, Volume 40, Issue 8, pp 1181–1188 | Cite as

UHRF2 promotes DNA damage response by decreasing p21 via RING finger domain

  • Yangyang Wang
  • Xinke Yan
  • Shengyuan Zeng
  • Ting Zhang
  • Fengjuan Cheng
  • Rongjuan Chen
  • Changzhu Duan
Original Research Paper



To investigate the interaction of E3 ubiquitin ligase UHRF2 with p21 and the mechanism of UHRF2 in repairing DNA damage caused by hydroxyurea (HU) in HEK293 cells.


Western blotting indicated that the overexpression of UHRF2 reduced the level of p21, particularly in HEK293 cells. Immunoprecipitation and immunofluorescence staining reveled that UHRF2 combined with p21 in the nucleus. In addition, UHRF2 degraded p21 through ubiquitination and shortened the half-life of p21. UHRF2 could repair DNA damage caused by HU treatment, which was impaired by the inhibition of p21 in HEK293 cells.


UHRF2 may negatively modulate p21 to regulate DNA damage response, suggesting a novel pathway of UHRF2 repairing DNA damage through the partial regulation of p21.


Degradation DNA damage response P21 Ubiquitination UHRF2 



This study was supported by National Natural Science Foundation of China (No. 81772178).

Supporting information

Supplementary Fig. 1—Structure diagrams of UHRF2 and the deletion mutants. The four main domains (UBL, PHD, SRA/YDG and RING) and a tandem Tudor (TTD) domain of UHRF2 were shown in diagrams. Four deletion mutants (ΔUBL, ΔPHD, ΔYDG and ΔRING) were created for this study.

Compliance with ethical standards

Conflict of interest

The authors declared no conflicts of interest.

Supplementary material

10529_2018_2577_MOESM1_ESM.docx (48 kb)
Supplementary material 1 (DOCX 47 kb)


  1. Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bendjennat M, Boulaire J, Jascur T, Brickner H, Barbier V, Sarasin A, Fotedar A, Fotedar R (2003) UV irradiation triggers ubiquitin-dependent degradation of p21 WAF1 to promote DNA repair. Cell 114:599–610CrossRefPubMedGoogle Scholar
  3. Chen X, Bosques L, Sung P, Kupfer GM (2016) A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage. Oncogene 35:22–34CrossRefPubMedGoogle Scholar
  4. Gu L, Gao W, Yang HM, Wang BB, Wang XN, Xu J, Zhang H (2016) Control of Trx1 redox state modulates protection against methyl methanesulfonate-induced DNA damage via stabilization of p21. J Biochem 159:101–110CrossRefPubMedGoogle Scholar
  5. Karimian A, Ahmadi Y, Yousefi B (2016) Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair 42:63–71CrossRefPubMedGoogle Scholar
  6. Krämer O, Knauer S, Zimmermann D, Stauber R, Heinzel T (2008) Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis. Oncogene 27:732–740CrossRefPubMedGoogle Scholar
  7. Luo T, Cui S, Bian C, Yu X (2013) Uhrf2 is important for DNA damage response in vascular smooth muscle cells. Biochem Biophys Res Commun 441:65–70CrossRefPubMedPubMedCentralGoogle Scholar
  8. Mauro M, Rego MA, Boisvert RA, Esashi F, Cavallo F, Jasin M, Howlett NG (2012) p21 promotes error-free replication-coupled DNA double-strand break repair. Nucleic Acids Res 40:8348–8360CrossRefPubMedPubMedCentralGoogle Scholar
  9. Mori T, Ikeda DD, Fukushima T, Takenoshita S, Kochi H (2011) NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor. Cell Cycle 10:3284–3299CrossRefPubMedPubMedCentralGoogle Scholar
  10. Valdiglesias V, Giunta S, Fenech M, Neri M, Bonassi S (2013) γH2AX as a marker of DNA double strand breaks and genomic instability in human population studies. Mutat Res 753:24–40CrossRefPubMedGoogle Scholar
  11. Wu J, Liu S, Liu G, Dombkowski A, Abrams J, Martin-Trevino R, Wicha M, Ethier S, Yang Z (2012) Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene 31:333–341CrossRefPubMedGoogle Scholar
  12. Zeng S, Wang Y, Zhang T, Bai L, Wang Y, Duan C (2017) E3 ligase UHRF2 stabilizes the acetyltransferase TIP60 and regulates H3K9ac and H3K14ac via RING finger domain. Protein Cell 8:202–218CrossRefPubMedGoogle Scholar
  13. Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R (2004) MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 279:16000–16006CrossRefPubMedGoogle Scholar
  14. Zhang L, Mei Y, N-y Fu, Guan L, Xie W, Liu H-h Yu, C-d Yin Z, Victor CY, You H (2012) TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21. Proc Natl Acad Sci 109:20937–20942CrossRefPubMedGoogle Scholar
  15. Zhi X, Zhao D, Wang Z, Zhou Z, Wang C, Chen W, Liu R, Chen C (2013) E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. Can Res 73:385–394CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Yangyang Wang
    • 1
  • Xinke Yan
    • 1
  • Shengyuan Zeng
    • 2
  • Ting Zhang
    • 3
  • Fengjuan Cheng
    • 1
  • Rongjuan Chen
    • 1
  • Changzhu Duan
    • 1
  1. 1.Department of Cell Biology and Genetics, Molecular Medicine and Cancer Research CenterChongqing Medical UniversityChongqingChina
  2. 2.Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics CenterLinkoping UniversityLinkopingSweden
  3. 3.Department of ObstetricsThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Personalised recommendations