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The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 1: post-translational regulation.

Vlachostergios PJ, Patrikidou A, Daliani DD, Papandreou CN - J. Cell. Mol. Med. (2009)

Bottom Line: DNA repair is a fundamental cellular function, indispensable for cell survival, especially in conditions of exposure to environmental or pharmacological effectors of DNA damage.The regulation of this function requires a flexible machinery to orchestrate the reversal of harmful DNA lesions by making use of existing proteins as well as inducible gene products.The accumulation of evidence for the involvement of ubiquitin-proteasome system (UPS) in DNA repair pathways, that is reviewed here, has expanded its role from a cellular waste disposal basket to a multi-dimensional regulatory system.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, University Hospital of Larissa, Larissa, Greece. pvlacho@med.uth.gr

ABSTRACT
DNA repair is a fundamental cellular function, indispensable for cell survival, especially in conditions of exposure to environmental or pharmacological effectors of DNA damage. The regulation of this function requires a flexible machinery to orchestrate the reversal of harmful DNA lesions by making use of existing proteins as well as inducible gene products. The accumulation of evidence for the involvement of ubiquitin-proteasome system (UPS) in DNA repair pathways, that is reviewed here, has expanded its role from a cellular waste disposal basket to a multi-dimensional regulatory system. This review is the first of two that attempt to illustrate the nature and interactions of all different DNA repair pathways where UPS is demonstrated to be involved, with special focus on cancer- and chemotherapy-related DNA-damage repair. In this first review, we will be presenting the proteolytic and non-proteolytic roles of UPS in the post-translational regulation of DNA repair proteins, while the second review will focus on the UPS-dependent transcriptional response of DNA repair after DNA damage and stress.

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Modes of UPS involvement in regulation of DNA repair. *Abbreviations: O6meG, O6-methylated guanine; MGMT, O6-methylguanine-DNA methyltransferase; DR, direct repair; hMSH2, human MutS homologue 2; hMSH6, human MutS homologue 6; hMLH1, human MutL homologue 1; hPMS2, human post-meiotic segregation increased 2 protein; MMR, mismatch-repair; NEDD8, neural precursor cell expressed, developmentally down-regulated 8; EXO I, human exonuclease 1; SSBs, single-strand breaks; DSBs, double-strand breaks; TDG, thymine-DNA glycosylase; APE, apurinic endonuclease; Lig 3, DNA-ligase 3; FEN1, flap structure-specific endonuclease 1; BER, base-excision repair; NER, nucleotide-excision repair; GGR, global genomic repair; TCR, transcription-coupled repair; CSN, COP9 signalosome; SUMO, small ubiquitin-like modifier; UNG2, uracil-DNA glycosylase 2; PARP-1, poly-ADP-ribose polymerase; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; XPC, Xeroderma pigmentosum complementation group C; HR23, homologue of Rad23; DDB1, damage-specific DNA binding protein 1; DDB2, damage-specific DNA binding protein 2; NEDD8, neural precursor cell expressed developmentally down-regulated 8; XPG, Xeroderma pigmentosum complementation group G; XPF, Xeroderma pigmentosum complementation group F; ERCC1, excision repair cross-complementing rodent repair deficiency complementation group 1; Lig 1, DNA-ligase 1; HR, homologous recombination; NHEJ, non-homologous end joining; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; Lig 4, DNA-ligase 4; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; PCNA, proliferating cell nuclear antigen protein; DSBR, double-strand break repair; MRN, Mre11-Rad50-Nbs1 complex; RPA, replication protein A; BRCA 1,2, breast cancer 1,2 genes; XRCC2, X-ray repair complementing defective repair in Chinese hamster cells 2; XRCC3; X-ray repair complementing defective repair in Chinese hamster cells 3; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; PRR, post-replication repair; TLS, translesion DNA synthesis; Pol η, DNA polymerase η; Pol ζ, DNA polymerase ζ; Pol γ, ɛ, DNA polymerases γ, ɛ; FANCC, Fanconi anaemia, complementation group C; FANCD2, Fanconi anaemia complementation group D2; FANCI, Fanconi anaemia complementation group I.
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fig01: Modes of UPS involvement in regulation of DNA repair. *Abbreviations: O6meG, O6-methylated guanine; MGMT, O6-methylguanine-DNA methyltransferase; DR, direct repair; hMSH2, human MutS homologue 2; hMSH6, human MutS homologue 6; hMLH1, human MutL homologue 1; hPMS2, human post-meiotic segregation increased 2 protein; MMR, mismatch-repair; NEDD8, neural precursor cell expressed, developmentally down-regulated 8; EXO I, human exonuclease 1; SSBs, single-strand breaks; DSBs, double-strand breaks; TDG, thymine-DNA glycosylase; APE, apurinic endonuclease; Lig 3, DNA-ligase 3; FEN1, flap structure-specific endonuclease 1; BER, base-excision repair; NER, nucleotide-excision repair; GGR, global genomic repair; TCR, transcription-coupled repair; CSN, COP9 signalosome; SUMO, small ubiquitin-like modifier; UNG2, uracil-DNA glycosylase 2; PARP-1, poly-ADP-ribose polymerase; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; XPC, Xeroderma pigmentosum complementation group C; HR23, homologue of Rad23; DDB1, damage-specific DNA binding protein 1; DDB2, damage-specific DNA binding protein 2; NEDD8, neural precursor cell expressed developmentally down-regulated 8; XPG, Xeroderma pigmentosum complementation group G; XPF, Xeroderma pigmentosum complementation group F; ERCC1, excision repair cross-complementing rodent repair deficiency complementation group 1; Lig 1, DNA-ligase 1; HR, homologous recombination; NHEJ, non-homologous end joining; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; Lig 4, DNA-ligase 4; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; PCNA, proliferating cell nuclear antigen protein; DSBR, double-strand break repair; MRN, Mre11-Rad50-Nbs1 complex; RPA, replication protein A; BRCA 1,2, breast cancer 1,2 genes; XRCC2, X-ray repair complementing defective repair in Chinese hamster cells 2; XRCC3; X-ray repair complementing defective repair in Chinese hamster cells 3; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; PRR, post-replication repair; TLS, translesion DNA synthesis; Pol η, DNA polymerase η; Pol ζ, DNA polymerase ζ; Pol γ, ɛ, DNA polymerases γ, ɛ; FANCC, Fanconi anaemia, complementation group C; FANCD2, Fanconi anaemia complementation group D2; FANCI, Fanconi anaemia complementation group I.

Mentions: In the issue of cancer cell-related resistance to chemotherapeutic drugs, there is striking evidence from recent literature that both Ub family members as signalling molecules and the proteasome, either as a full entity (26S) or through its constituent subunits (20S, 19S) with distinct roles, proteolytic and non-proteolytic, are strong regulators of the DNA repair machinery. The complexity of UPS-DNA repair connection includes post-translational as well as transcriptional modifications of many repair proteins (Fig. 1). The DNA repair processes are reviewed here in the context of post-translational modifications induced by UPS (Fig. 2, Table 1), in an effort to offer a perspective of better understanding the profile of underlying mechanisms but also discover the utility and contribution of proteasome inhibitors to the reversal of DNA repair, which is an important matter in relation to therapeutic outcome, in terms of their expanding use in the treatment of malignancies, alone or in combination with other antineoplastic drugs, notably DNA-damaging agents.


The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 1: post-translational regulation.

Vlachostergios PJ, Patrikidou A, Daliani DD, Papandreou CN - J. Cell. Mol. Med. (2009)

Modes of UPS involvement in regulation of DNA repair. *Abbreviations: O6meG, O6-methylated guanine; MGMT, O6-methylguanine-DNA methyltransferase; DR, direct repair; hMSH2, human MutS homologue 2; hMSH6, human MutS homologue 6; hMLH1, human MutL homologue 1; hPMS2, human post-meiotic segregation increased 2 protein; MMR, mismatch-repair; NEDD8, neural precursor cell expressed, developmentally down-regulated 8; EXO I, human exonuclease 1; SSBs, single-strand breaks; DSBs, double-strand breaks; TDG, thymine-DNA glycosylase; APE, apurinic endonuclease; Lig 3, DNA-ligase 3; FEN1, flap structure-specific endonuclease 1; BER, base-excision repair; NER, nucleotide-excision repair; GGR, global genomic repair; TCR, transcription-coupled repair; CSN, COP9 signalosome; SUMO, small ubiquitin-like modifier; UNG2, uracil-DNA glycosylase 2; PARP-1, poly-ADP-ribose polymerase; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; XPC, Xeroderma pigmentosum complementation group C; HR23, homologue of Rad23; DDB1, damage-specific DNA binding protein 1; DDB2, damage-specific DNA binding protein 2; NEDD8, neural precursor cell expressed developmentally down-regulated 8; XPG, Xeroderma pigmentosum complementation group G; XPF, Xeroderma pigmentosum complementation group F; ERCC1, excision repair cross-complementing rodent repair deficiency complementation group 1; Lig 1, DNA-ligase 1; HR, homologous recombination; NHEJ, non-homologous end joining; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; Lig 4, DNA-ligase 4; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; PCNA, proliferating cell nuclear antigen protein; DSBR, double-strand break repair; MRN, Mre11-Rad50-Nbs1 complex; RPA, replication protein A; BRCA 1,2, breast cancer 1,2 genes; XRCC2, X-ray repair complementing defective repair in Chinese hamster cells 2; XRCC3; X-ray repair complementing defective repair in Chinese hamster cells 3; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; PRR, post-replication repair; TLS, translesion DNA synthesis; Pol η, DNA polymerase η; Pol ζ, DNA polymerase ζ; Pol γ, ɛ, DNA polymerases γ, ɛ; FANCC, Fanconi anaemia, complementation group C; FANCD2, Fanconi anaemia complementation group D2; FANCI, Fanconi anaemia complementation group I.
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fig01: Modes of UPS involvement in regulation of DNA repair. *Abbreviations: O6meG, O6-methylated guanine; MGMT, O6-methylguanine-DNA methyltransferase; DR, direct repair; hMSH2, human MutS homologue 2; hMSH6, human MutS homologue 6; hMLH1, human MutL homologue 1; hPMS2, human post-meiotic segregation increased 2 protein; MMR, mismatch-repair; NEDD8, neural precursor cell expressed, developmentally down-regulated 8; EXO I, human exonuclease 1; SSBs, single-strand breaks; DSBs, double-strand breaks; TDG, thymine-DNA glycosylase; APE, apurinic endonuclease; Lig 3, DNA-ligase 3; FEN1, flap structure-specific endonuclease 1; BER, base-excision repair; NER, nucleotide-excision repair; GGR, global genomic repair; TCR, transcription-coupled repair; CSN, COP9 signalosome; SUMO, small ubiquitin-like modifier; UNG2, uracil-DNA glycosylase 2; PARP-1, poly-ADP-ribose polymerase; XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1; XPC, Xeroderma pigmentosum complementation group C; HR23, homologue of Rad23; DDB1, damage-specific DNA binding protein 1; DDB2, damage-specific DNA binding protein 2; NEDD8, neural precursor cell expressed developmentally down-regulated 8; XPG, Xeroderma pigmentosum complementation group G; XPF, Xeroderma pigmentosum complementation group F; ERCC1, excision repair cross-complementing rodent repair deficiency complementation group 1; Lig 1, DNA-ligase 1; HR, homologous recombination; NHEJ, non-homologous end joining; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; Lig 4, DNA-ligase 4; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; PCNA, proliferating cell nuclear antigen protein; DSBR, double-strand break repair; MRN, Mre11-Rad50-Nbs1 complex; RPA, replication protein A; BRCA 1,2, breast cancer 1,2 genes; XRCC2, X-ray repair complementing defective repair in Chinese hamster cells 2; XRCC3; X-ray repair complementing defective repair in Chinese hamster cells 3; XRCC4, X-ray repair complementing defective repair in Chinese hamster cells 4; PRR, post-replication repair; TLS, translesion DNA synthesis; Pol η, DNA polymerase η; Pol ζ, DNA polymerase ζ; Pol γ, ɛ, DNA polymerases γ, ɛ; FANCC, Fanconi anaemia, complementation group C; FANCD2, Fanconi anaemia complementation group D2; FANCI, Fanconi anaemia complementation group I.
Mentions: In the issue of cancer cell-related resistance to chemotherapeutic drugs, there is striking evidence from recent literature that both Ub family members as signalling molecules and the proteasome, either as a full entity (26S) or through its constituent subunits (20S, 19S) with distinct roles, proteolytic and non-proteolytic, are strong regulators of the DNA repair machinery. The complexity of UPS-DNA repair connection includes post-translational as well as transcriptional modifications of many repair proteins (Fig. 1). The DNA repair processes are reviewed here in the context of post-translational modifications induced by UPS (Fig. 2, Table 1), in an effort to offer a perspective of better understanding the profile of underlying mechanisms but also discover the utility and contribution of proteasome inhibitors to the reversal of DNA repair, which is an important matter in relation to therapeutic outcome, in terms of their expanding use in the treatment of malignancies, alone or in combination with other antineoplastic drugs, notably DNA-damaging agents.

Bottom Line: DNA repair is a fundamental cellular function, indispensable for cell survival, especially in conditions of exposure to environmental or pharmacological effectors of DNA damage.The regulation of this function requires a flexible machinery to orchestrate the reversal of harmful DNA lesions by making use of existing proteins as well as inducible gene products.The accumulation of evidence for the involvement of ubiquitin-proteasome system (UPS) in DNA repair pathways, that is reviewed here, has expanded its role from a cellular waste disposal basket to a multi-dimensional regulatory system.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, University Hospital of Larissa, Larissa, Greece. pvlacho@med.uth.gr

ABSTRACT
DNA repair is a fundamental cellular function, indispensable for cell survival, especially in conditions of exposure to environmental or pharmacological effectors of DNA damage. The regulation of this function requires a flexible machinery to orchestrate the reversal of harmful DNA lesions by making use of existing proteins as well as inducible gene products. The accumulation of evidence for the involvement of ubiquitin-proteasome system (UPS) in DNA repair pathways, that is reviewed here, has expanded its role from a cellular waste disposal basket to a multi-dimensional regulatory system. This review is the first of two that attempt to illustrate the nature and interactions of all different DNA repair pathways where UPS is demonstrated to be involved, with special focus on cancer- and chemotherapy-related DNA-damage repair. In this first review, we will be presenting the proteolytic and non-proteolytic roles of UPS in the post-translational regulation of DNA repair proteins, while the second review will focus on the UPS-dependent transcriptional response of DNA repair after DNA damage and stress.

Show MeSH
Related in: MedlinePlus