BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase with tumor suppressor activity. The gene encoding BAP1 is mutated in various human cancers, with particularly high frequency in kidney and skin cancers, and BAP1 is involved in many cancer-related cellular functions, such as DNA repair and genome stability. Although BAP1 stimulates DNA double-strand break repair, whether it functions in nucleotide excision repair (NER) is unknown. Here, we show that BAP1 promotes the repair of ultraviolet (UV)-induced DNA damage via its deubiquitination activity in various cell types, including primary melanocytes. Poly(ADP-ribose) polymerase 1 (PARP1) interacts with and recruits BAP1 to damage sites, with BAP1 recruitment peaking after the DDB2 and XPC damage sensors. BAP1 recruitment also requires histone H2A monoubiquitinated at Lys119, which accumulates at damage sites. PARP1 transiently poly(ADP-ribosyl)ates (PARylates) BAP1 at multiple sites after UV damage and stimulates the deubiquitination activity of BAP1 both intrinsically and via PARylation. PARP1 also promotes BAP1 stability via crosstalk between PARylation and ubiquitination. Many PARylation sites in BAP1 are mutated in various human cancers, among which the glutamic acid (Glu) residue at position 31, with particularly frequent mutation in kidney cancer, plays a critical role in BAP1 stabilization and promotes UV-induced DNA damage repair. Glu31 also participates in reducing the viability of kidney cancer cells. This study therefore reveals that BAP1 functions in the NER pathway and that PARP1 plays a role as a novel factor that regulates BAP1 enzymatic activity, protein stability, and recruitment to damage sites. This activity of BAP1 in NER, along with its cancer cell viability-reducing activity, may account for its tumor suppressor function.
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Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15:465–81.
Sugasawa K. Molecular mechanisms of DNA damage recognition for mammalian nucleotide excision repair. DNA Repair. 2016;44:110–7.
Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017;18:610–21.
Kraus WL. PARPs and ADP-Ribosylation: 50 Years … and Counting. Mol Cell. 2015;58:902–10.
Cohen MS, Chang P. Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol. 2018;14:236–43.
Gupte R, Liu Z, Kraus WL. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes & development. 2017;31:101–26.
Alemasova EE, Lavrik OI. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins. Nucleic Acids Res. 2019;47:3811–27.
Robu M, Shah RG, Purohit NK, Zhou P, Naegeli H, Shah GM. Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair. Proc Natl Acad Sci USA. 2017;114:E6847–E6856.
Robu M, Shah RG, Petitclerc N, Brind'Amour J, Kandan-Kulangara F, Shah GM. Role of poly(ADP-ribose) polymerase-1 in the removal of UV-induced DNA lesions by nucleotide excision repair. Proc Natl Acad Sci USA. 2013;110:1658–63.
Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, et al. PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1. J Cell Biol. 2012;199:235–49.
King BS, Cooper KL, Liu KJ, Hudson LG. Poly(ADP-ribose) contributes to an association between poly(ADP-ribose) polymerase-1 and xeroderma pigmentosum complementation group A in nucleotide excision repair. J Biol Chem. 2012;287:39824–33.
Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16:1097–112.
Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. BAP1 and cancer. Nat Rev Cancer. 2013;13:153–9.
Masclef L, Ahmed O, Estavoyer B, Larrivee B, Labrecque N, Nijnik A, et al. Roles and mechanisms of BAP1 deubiquitinase in tumor suppression. Cell Death Differ. 2021;28:606–25.
Szczepanski AP, Wang L. Emerging multifaceted roles of BAP1 complexes in biological processes. Cell Death Disco. 2021;7:20.
Abdel-Rahman MH, Pilarski R, Cebulla CM, Massengill JB, Christopher BN, Boru G, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011;48:856–9.
Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet. 2011;43:668–72.
Guo G, Gui Y, Gao S, Tang A, Hu X, Huang Y, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet. 2012;44:17–19.
Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330:1410–3.
Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44:751–9.
Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43:1022–5.
Carbone M, Adusumilli PS, Alexander HR Jr, Baas P, Bardelli F, Bononi A, et al. Mesothelioma: Scientific clues for prevention, diagnosis, and therapy. CA Cancer J Clin. 2019;69:402–29.
Napolitano A, Pellegrini L, Dey A, Larson D, Tanji M, Flores EG, et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2016;35:1996–2002.
Kadariya Y, Cheung M, Xu J, Pei J, Sementino E, Menges CW, et al. Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations. Cancer Res. 2016;76:2836–44.
Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, Sementino E, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74:4388–97.
Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science. 2012;337:1541–6.
Machida YJ, Machida Y, Vashisht AA, Wohlschlegel JA, Dutta A. The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1. J Biol Chem. 2009;284:34179–88.
Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, et al. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol. 2009;29:2181–92.
Eletr ZM, Wilkinson KD. An emerging model for BAP1's role in regulating cell cycle progression. Cell Biochem Biophys. 2011;60:3–11.
Affar EB, Carbone M. BAP1 regulates different mechanisms of cell death. Cell Death Dis. 2018;9:1151.
Yu H, Pak H, Hammond-Martel I, Ghram M, Rodrigue A, Daou S, et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc Natl Acad Sci USA. 2014;111:285–90.
Eletr ZM, Yin L, Wilkinson KD. BAP1 is phosphorylated at serine 592 in S-phase following DNA damage. FEBS Lett. 2013;587:3906–11.
Klusmann I, Wohlberedt K, Magerhans A, Teloni F, Korbel JO, Altmeyer M, et al. Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication. Proc Natl Acad Sci USA. 2018;115:E11311–E11320.
Lee HS, Lee SA, Hur SK, Seo JW, Kwon J. Stabilization and targeting of INO80 to replication forks by BAP1 during normal DNA synthesis. Nat Commun. 2014;5:5128.
Lee HS, Seo HR, Lee SA, Choi S, Kang D, Kwon J. BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress. Biochemical J. 2019;476:3053–66.
Peng J, Ma J, Li W, Mo R, Zhang P, Gao K, et al. Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma. Cancer Lett. 2015;369:167–74.
Ismail IH, Davidson R, Gagne JP, Xu ZZ, Poirier G, Hendzel MJ Germ-line Mutations in BAP1 Impair its Function in DNA Double-Strand break Repair. Cancer Res. 2014.
Muster B, Rapp A, Cardoso MC. Systematic analysis of DNA damage induction and DNA repair pathway activation by continuous wave visible light laser micro-irradiation. AIMS Genet. 2017;4:47–68.
Wakasugi M, Sasaki T, Matsumoto M, Nagaoka M, Inoue K, Inobe M, et al. Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells. J Biol Chem. 2014;289:28730–7.
Ray A, Milum K, Battu A, Wani G, Wani AA. NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites. DNA Repair. 2013;12:273–83.
Zhang Y, Wang J, Ding M, Yu Y. Site-specific characterization of the Asp- and Glu-ADP-ribosylated proteome. Nat Methods. 2013;10:981–4.
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012;13:411–24.
Bergink S, Salomons FA, Hoogstraten D, Groothuis TA, de Waard H, Wu J, et al. DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A. Genes Dev. 2006;20:1343–52.
Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS. The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites. Proc Natl Acad Sci USA. 2006;103:2588–93.
Zhu Q, Wani G, Arab HH, El-Mahdy MA, Ray A, Wani AA. Chromatin restoration following nucleotide excision repair involves the incorporation of ubiquitinated H2A at damaged genomic sites. DNA Repair. 2009;8:262–73.
Chitale S, Richly HDICER. and ZRF1 contribute to chromatin decondensation during nucleotide excision repair. Nucleic Acids Res. 2017;45:5901–12.
Marteijn JA, Bekker-Jensen S, Mailand N, Lans H, Schwertman P, Gourdin AM, et al. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. Cell Biol. 2009;186:835–47.
Sarkar S, Kiely R, McHugh PJ. The Ino80 chromatin-remodeling complex restores chromatin structure during UV DNA damage repair. J Cell Biol. 2010;191:1061–8.
Jiang Y, Wang X, Bao S, Guo R, Johnson DG, Shen X, et al. INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway. Proc Natl Acad Sci USA. 2010;107:17274–9.
Rathkey D, Khanal M, Murai J, Zhang J, Sengupta M, Jiang Q, et al. Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression. J Thorac Oncol. 2020;15:843–59.
Carbone M, Pass HI, Ak G, Alexander HR Jr, Baas P, Baumann F, et al. Medical and surgical care of mesothelioma patients and their relatives carrying germline BAP1 mutations. J Thorac Oncol. 2022;S1556-0864:00192–7.
Ghafoor A, Mian I, Wagner C, Mallory Y, Agra MG, Morrow B, et al. Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1. Gene. JTO Clin Res Rep. 2021;2:100231.
Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, et al. BAP1 regulates IP3R3-mediated Ca(2+) flux to mitochondria suppressing cell transformation. Nature. 2017;546:549–53.
Sime W, Niu Q, Abassi Y, Masoumi KC, Zarrizi R, Kohler JB, et al. BAP1 induces cell death via interaction with 14-3-3 in neuroblastoma. Cell Death Dis. 2018;9:458.
He M, Chaurushiya MS, Webster JD, Kummerfeld S, Reja R, Chaudhuri S, et al. Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1. Science. 2019;364:283–5.
Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018;20:1181–92.
Lee JW, Kim JE, Park EJ, Kim JH, Lee CH, Lee SR, et al. Two conserved cysteine residues are critical for the enzymic function of the human platelet-derived growth factor receptor-beta: evidence for different roles of Cys-822 and Cys-940 in the kinase activity. Biochem J. 2004;382:631–9.
Lee D, Lee DY, Hwang YS, Seo HR, Lee SA, Kwon J. The Bromodomain Inhibitor PFI-3 Sensitizes Cancer Cells to DNA Damage by Targeting SWI/SNF. Mol Cancer Res: MCR. 2021;19:900–12.
Robu M, Shah RG, Shah GM. Methods to Study Intracellular Movement and Localization of the Nucleotide Excision Repair Proteins at the DNA Lesions in Mammalian Cells. Front Cell Dev Biol. 2020;8:590242.
Park SG, Lee D, Seo HR, Lee SA, Kwon J. Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells. Sci Rep. 2020;10:16330.
Sahtoe DD, van Dijk WJ, Ekkebus R, Ovaa H, Sixma TK. BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat Commun. 2016;7:10292.
Mashtalir N, Daou S, Barbour H, Sen NN, Gagnon J, Hammond-Martel I, et al. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol Cell. 2014;54:392–406.
Seo HR, Jeong D, Lee S, Lee HS, Lee SA, Kang SW, et al. CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication. Molecules Cells. 2021;44:101–15.
Soo Lee N, Jin Chung H, Kim HJ, Yun Lee S, Ji JH, Seo Y, et al. TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage. Nat Commun. 2016;7:10463.
We thank Mi Young Kim and William Kraus for providing the pQCXIH-PARP1-His6/FLAG vector. Funding: This work was supported by grants 2021R1A2C1008613, 2019R1A5A6099645 and 2017M3A9F9030559 from the National Research Foundation of Korea.
This work was supported by grants 2021R1A2C1008613, 2019R1A5A6099645 and 2017M3A9F9030559 from the National Research Foundation of Korea.
The authors declare no competing interests.
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Lee, SA., Lee, D., Kang, M. et al. BAP1 promotes the repair of UV-induced DNA damage via PARP1-mediated recruitment to damage sites and control of activity and stability. Cell Death Differ 29, 2381–2398 (2022). https://doi.org/10.1038/s41418-022-01024-w
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