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http://dx.doi.org/10.14348/molcells.2018.0078

A Novel Reciprocal Crosstalk between RNF168 and PARP1 to Regulate DNA Repair Processes  

Kim, Jae Jin (Genomic Instability Research Center, Ajou University School of Medicine)
Lee, Seo Yun (Genomic Instability Research Center, Ajou University School of Medicine)
Kim, Soyeon (Genomic Instability Research Center, Ajou University School of Medicine)
Chung, Jee Min (Genomic Instability Research Center, Ajou University School of Medicine)
Kwon, Mira (Genomic Instability Research Center, Ajou University School of Medicine)
Yoon, Jung Hyun (Genomic Instability Research Center, Ajou University School of Medicine)
Park, Sangwook (Genomic Instability Research Center, Ajou University School of Medicine)
Hwang, Yiseul (Genomic Instability Research Center, Ajou University School of Medicine)
Park, Dongsun (Genomic Instability Research Center, Ajou University School of Medicine)
Lee, Jong-Soo (Genomic Instability Research Center, Ajou University School of Medicine)
Kang, Ho Chul (Genomic Instability Research Center, Ajou University School of Medicine)
Publication Information
Molecules and Cells / v.41, no.8, 2018 , pp. 799-807 More about this Journal
Abstract
Emerging evidence has suggested that cellular crosstalk between RNF168 and poly(ADP-ribose) polymerase 1 (PARP1) contributes to the precise control of the DNA damage response (DDR). However, the direct and reciprocal functional link between them remains unclear. In this report, we identified that RNF168 ubiquitinates PARP1 via direct interaction and accelerates PARP1 degradation in the presence of poly (ADP-ribose) (PAR) chains, metabolites of activated PARP1. Through mass spectrometric analysis, we revealed that RNF168 ubiquitinated multiple lysine residues on PARP1 via K48-linked ubiquitin chain formation. Consistent with this, micro-irradiation-induced PARP1 accumulation at damaged chromatin was significantly increased by knockdown of endogenous RNF168. In addition, it was confirmed that abnormal changes of HR and HNEJ due to knockdown of RNF168 were restored by overexpression of WT RNF168 but not by reintroduction of mutants lacking E3 ligase activity or PAR binding ability. The comet assay also revealed that both PAR-binding and ubiquitin-conjugation activities are indispensable for the RNF168-mediated DNA repair process. Taken together, our results suggest that RNF168 acts as a counterpart of PARP1 in DDR and regulates the HR/NHEJ repair processes through the ubiquitination of PARP1.
Keywords
DNA repair; PARP1; PARylation; RNF168; ubiquitination;
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1 Andrabi, S.A., Kang, H.C., Haince, J.F., Lee ,Y,I., Zhang, J., Chi, Z., West, A.B., Koehler, R.C., Poirier, G.G., Dawson, T.M., et al. (2011). Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat. Med. 17, 692-699.   DOI
2 Ciccia, A., and Elledge, S.J. (2010). The DNA damage response: making it safe to play with knives. Mol. Cell. 40, 179-204.   DOI
3 David, K.K., Andrabi, S.A., Dawson, T.M., Dawson, V.L. (2009). Parthanatos, a messenger of death. Front Biosci (Landmark Ed). 14, 1116-28.
4 Gatti, M., Pinato, S., Maiolica, A., Rocchio, F., Prato, M.G., Aebersold R., and Penengo, L. (2015). RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep. 10, 226-238.   DOI
5 Gibson, B.A., and Kraus, W.L. (2012). New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411-424.   DOI
6 Lee, Y., Karuppagounder, S.S., Shin, J.H., Lee, Y.I., Ko, H.S., Swing, D., Jiang, H., Kang, S.U., Lee, B.D., Kang, H.C., et al. (2013). Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392-1400.   DOI
7 Gudjonsson, T., Altmeyer, M., Savic, V., Toledo, L., Dinant, C., Grofte, M., Bartkova, J., Poulsen, M., Oka, Y., Bekker-Jensen, S., et al. (2012). TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell 150, 697-709.   DOI
8 Haince, J.F., Kozlov, S., Dawson, V.L., Dawson, T.M., Hendzel, M.J., Lavin, M.F., and Poirier, G.G. (2007). Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J. Biol. Chem. 282, 16441-16453.   DOI
9 Kulkarni, A., and Wilson, D.M., 3rd. (2008). The involvement of DNA-damage and -repair defects in neurological dysfunction. Am. J. Hum. Genet. 82, 539-66.   DOI
10 Lord, C.J., and shworth, A. (2012). The DNA damage response and cancer therapy. Nature 481, 287-294.   DOI
11 Luo, X., and Kraus, W.L. (2012). On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 26, 417-432.   DOI
12 Marecki, J.C., and McCord, J.M. (2002). The inhibition of poly(ADPribose) polymerase enhances growth rates of ataxia telangiectasia cells. Arch. Biochem. Biophys. 402, 227-234.   DOI
13 Mattiroli, F., Vissers, J.H., van Dijk, W.J., Ikpa, P., Citterio, E., Vermeulen, W., Marteijn, J.A., and Sixma, T.K. (2012). RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182-1195.   DOI
14 Smeenk, G., Wiegant, W.W., Marteijn, J.A., Luijsterburg, M.S., Sroczynski, N., Costelloe, T., Romeijn, R.J., Pastink, A., Mailand, N., Vermeulen, W., et al. (2013). Poly(ADP-ribosyl)ation links the chromatin remodeler SMARCA5/SNF2H to RNF168-dependent DNA damage signaling. J. Cell Sci. 126, 889-903.   DOI
15 Polo, S.E., and Jackson, S.P. (2011). Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409-433.   DOI
16 Rass, U., Ahel, I., and West, S.C. (2007). Defective DNA repair and neurodegenerative disease. Cell 130, 991-1004.   DOI
17 Schwertman, P., Bekker-Jensen, S., and Mailand, N. (2016). Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat. Rev. Mol. Cell Biol. 17, 379-394.   DOI
18 Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman, L., and Shiloh, Y. (2003). Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 22, 5612-5621.   DOI
19 Wei, H., and Yu, X. (2016). Functions of PARylation in DNA damage repair pathways. Genomics Proteomics Bioinformatics. 14, 131-139.   DOI
20 You, Z., Chahwan, C., Bailis, J., Hunter, T., and Russell, P. (2005). ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol. Cell Biol. 25, 5363-5379.   DOI