Skip to main content
PMC home page
Protein & Cell logoLink to Protein & Cell
. 2010 Jul 7;1(6):573–583. doi: 10.1007/s13238-010-0075-1

p38γ regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage

Chia-Cheng Wu 1, Xiaohua Wu 2, Jiahuai Han 1,3,✉, Peiqing Sun 4,✉
PMCID: PMC3002048  NIHMSID: NIHMS220732  PMID: 21170151

Abstract

In eukaryotic cells, DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA. These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer. The p38 MAPK was previously implicated in cellular responses to several types of DNA damage. However, the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood. In this study, we demonstrate that p38γ, but not the other p38 isoforms, contributes to the survival of UV-treated cells. Deletion of p38γ sensitizes cells to UV exposure, accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis. Further investigation reveal that p38γ is essential for the optimal activation of the checkpoint signaling caused by UV, and for the efficient repair of UV-induced DNA damage. These findings have established a novel role of p38γ in UV-induced DNA damage responses, and suggested that p38γ contributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-010-0075-1 and is accessible for authorized users.

Keywords: p38γ, DNA damage, UV, DNA repair, checkpoint signaling

Electronic supplementary material

13238_2010_75_MOESM1_ESM.pdf (289.4KB, pdf)

Supplementary material, approximately 340 KB.

Footnotes

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s13238-010-0075-1 and is accessible for authorized users.

Contributor Information

Jiahuai Han, Email: jhan@scripps.edu.

Peiqing Sun, Email: pqsun@scripps.edu.

References

  1. Abraham R.T. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001;15:2177–2196. doi: 10.1101/gad.914401. [DOI] [PubMed] [Google Scholar]
  2. Beardmore V.A., Hinton H.J., Eftychi C., Apostolaki M., Armaka M., Darragh J., McIlrath J., Carr J.M., Armit L.J., Clacher C., et al. Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol. 2005;25:10454–10464. doi: 10.1128/MCB.25.23.10454-10464.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bomgarden R.D., Lupardus P.J., Soni D.V., Yee M.C., Ford J.M., Cimprich K.A. Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling. EMBO J. 2006;25:2605–2614. doi: 10.1038/sj.emboj.7601123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bulavin D.V., Higashimoto Y., Popoff I.J., Gaarde W.A., Basrur V., Potapova O., Appella E., Fornace A.J., Jr. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature. 2001;411:102–107. doi: 10.1038/35075107. [DOI] [PubMed] [Google Scholar]
  5. Bulavin D.V., Saito S., Hollander M.C., Sakaguchi K., Anderson C.W., Appella E., Fornace A.J., Jr. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 1999;18:6845–6854. doi: 10.1093/emboj/18.23.6845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cimprich K.A., Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008;9:616–627. doi: 10.1038/nrm2450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cline S.D., Hanawalt P.C. Who’s on first in the cellular response to DNA damage? Nat Rev Mol Cell Biol. 2003;4:361–372. doi: 10.1038/nrm1101. [DOI] [PubMed] [Google Scholar]
  8. Dent P., Yacoub A., Fisher P.B., Hagan M.P., Grant S. MAPK pathways in radiation responses. Oncogene. 2003;22:5885–5896. doi: 10.1038/sj.onc.1206701. [DOI] [PubMed] [Google Scholar]
  9. Enslen H., Brancho D.M., Davis R.J. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000;19:1301–1311. doi: 10.1093/emboj/19.6.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gatei M., Young D., Cerosaletti K.M., Desai-Mehta A., Spring K., Kozlov S., Lavin M.F., Gatti R.A., Concannon P., Khanna K. ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet. 2000;25:115–119. doi: 10.1038/75508. [DOI] [PubMed] [Google Scholar]
  11. Han J., Lee J.D., Bibbs L., Ulevitch R.J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994;265:808–811. doi: 10.1126/science.7914033. [DOI] [PubMed] [Google Scholar]
  12. Han J., Sun P. The pathways to tumor suppression via route p38. Trends Biochem Sci. 2007;32:364–371. doi: 10.1016/j.tibs.2007.06.007. [DOI] [PubMed] [Google Scholar]
  13. Hirose Y., Katayama M., Stokoe D., Haas-Kogan D.A., Berger M. S., Pieper R.O. The p38 mitogen-activated protein kinase pathway links the DNA mismatch repair system to the G2 checkpoint and to resistance to chemotherapeutic DNA-methylating agents. Mol Cell Biol. 2003;23:8306–8315. doi: 10.1128/MCB.23.22.8306-8315.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hu W., Feng Z., Tang M.S. Nickel (II) enhances benzo [a]pyrene diol epoxide-induced mutagenesis through inhibition of nucleotide excision repair in human cells: a possible mechanism for nickel (II)-induced carcinogenesis. Carcinogenesis. 2004;25:455–462. doi: 10.1093/carcin/bgh012. [DOI] [PubMed] [Google Scholar]
  15. Jia L., Wang X.W., Harris C.C. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer. 1999;80:875–879. doi: 10.1002/(SICI)1097-0215(19990315)80:6<875::AID-IJC13>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  16. Jiang Y., Chen C., Li Z., Guo W., Gegner J.A., Lin S., Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta) J Biol Chem. 1996;271:17920–17926. doi: 10.1074/jbc.271.30.17920. [DOI] [PubMed] [Google Scholar]
  17. Jiang Y., Gram H., Zhao M., New L., Gu J., Feng L., Di Padova F., Ulevitch R.J., Han J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem. 1997;272:30122–30128. doi: 10.1074/jbc.272.48.30122. [DOI] [PubMed] [Google Scholar]
  18. Johnson G.L., Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911–1912. doi: 10.1126/science.1072682. [DOI] [PubMed] [Google Scholar]
  19. Kang Y.J., Chen J., Otsuka M., Mols J., Ren S., Wang Y., Han J. Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol. 2008;180:5075–5082. doi: 10.4049/jimmunol.180.7.5075. [DOI] [PubMed] [Google Scholar]
  20. Kastan M.B., Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–323. doi: 10.1038/nature03097. [DOI] [PubMed] [Google Scholar]
  21. Latonen L., Laiho M. Cellular UV damage responses—functions of tumor suppressor p53. Biochim Biophys Acta. 2005;1755:71–89. doi: 10.1016/j.bbcan.2005.04.003. [DOI] [PubMed] [Google Scholar]
  22. Li Z., Jiang Y., Ulevitch R.J., Han J. The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996;228:334–340. doi: 10.1006/bbrc.1996.1662. [DOI] [PubMed] [Google Scholar]
  23. Lim D.S., Kim S.T., Xu B., Maser R.S., Lin J., Petrini J.H., Kastan M.B. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature. 2000;404:613–617. doi: 10.1038/35007091. [DOI] [PubMed] [Google Scholar]
  24. Manke I.A., Nguyen A., Lim D., Stewart M.Q., Elia A.E., Yaffe M.B. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005;17:37–48. doi: 10.1016/j.molcel.2004.11.021. [DOI] [PubMed] [Google Scholar]
  25. Nebreda A.R., Porras A. p38 MAP kinases: beyond the stress response. Trends Biochem Sci. 2000;25:257–260. doi: 10.1016/S0968-0004(00)01595-4. [DOI] [PubMed] [Google Scholar]
  26. Olson E., Nievera C.J., Lee A.Y., Chen L., Wu X. The Mre11-Rad50-Nbs1 complex acts both upstream and downstream of ataxia telangiectasia mutated and Rad3-related protein (ATR) to regulate the S-phase checkpoint following UV treatment. J Biol Chem. 2007;282:22939–22952. doi: 10.1074/jbc.M702162200. [DOI] [PubMed] [Google Scholar]
  27. Ono K., Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13. doi: 10.1016/S0898-6568(99)00071-6. [DOI] [PubMed] [Google Scholar]
  28. Otsuka M., Kang Y.J., Ren J., Jiang H., Wang Y., Omata M., Han J. Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology. 2010;138:1255–65. doi: 10.1053/j.gastro.2010.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Raman M., Earnest S., Zhang K., Zhao Y., Cobb M.H. TAO kinases mediate activation of p38 in response to DNA damage. EMBO J. 2007;26:2005–2014. doi: 10.1038/sj.emboj.7601668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sabio G., Arthur J.S., Kuma Y., Peggie M., Carr J., Murray-Tait V., Centeno F., Goedert M., Morrice N.A., Cuenda A. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24:1134–1145. doi: 10.1038/sj.emboj.7600578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593–602. doi: 10.1016/S0092-8674(00)81902-9. [DOI] [PubMed] [Google Scholar]
  32. She Q.B., Chen N., Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J Biol Chem. 2000;275:20444–20449. doi: 10.1074/jbc.M001020200. [DOI] [PubMed] [Google Scholar]
  33. Shi Y., Gaestel M. In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem. 2002;383:1519–1536. doi: 10.1515/BC.2002.173. [DOI] [PubMed] [Google Scholar]
  34. Sun P., Dong P., Dai K., Hannon G.J., Beach D. p53-independent role of MDM2 in TGF-beta1 resistance. Science. 1998;282:2270–2272. doi: 10.1126/science.282.5397.2270. [DOI] [PubMed] [Google Scholar]
  35. Tanoue T., Yamamoto T., Maeda R., Nishida E. A novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem. 2001;276:26629–26639. doi: 10.1074/jbc.M101981200. [DOI] [PubMed] [Google Scholar]
  36. Tibbetts R.S., Brumbaugh K.M., Williams J.M., Sarkaria J.N., Cliby W.A., Shieh S.Y., Taya Y., Prives C., Abraham R.T. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999;13:152–157. doi: 10.1101/gad.13.2.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. van Attikum H., Gasser S.M. Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol. 2009;19:207–217. doi: 10.1016/j.tcb.2009.03.001. [DOI] [PubMed] [Google Scholar]
  38. Wang X., McGowan C.H., Zhao M., He L., Downey J.S., Fearns C., Wang Y., Huang S., Han J. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20:4543–4552. doi: 10.1128/MCB.20.13.4543-4552.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wu X., Ranganathan V., Weisman D.S., Heine W.F., Ciccone D.N., O’Neill T.B., Crick K.E., Pierce K.A., Lane W.S., Rathbun G., et al. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature. 2000;405:477–482. doi: 10.1038/35013089. [DOI] [PubMed] [Google Scholar]
  40. Zhao Q., Barakat B.M., Qin S., Ray A., El-Mahdy M.A., Wani G., Arafa S., Mir S.N., Wang Q.E., Wani A.A. The p38 mitogen-activated protein kinase augments nucleotide excision repair by mediating DDB2 degradation and chromatin relaxation. J Biol Chem. 2008;283:32553–32561. doi: 10.1074/jbc.M803963200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zhao S., Weng Y.C., Yuan S.S., Lin Y.T., Hsu H.C., Lin S.C., Gerbino E., Song M.H., Zdzienicka M.Z., Gatti R.A., et al. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature. 2000;405:473–477. doi: 10.1038/35013083. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

13238_2010_75_MOESM1_ESM.pdf (289.4KB, pdf)

Supplementary material, approximately 340 KB.

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES