The NR4A2 Nuclear Receptor Is Recruited to Novel Nuclear Foci in Response to UV Irradiation and Participates in Nucleotide Excision Repair

Regulation of DNA repair can be achieved through ubiquitin-mediated degradation of transiently induced proteins. In Saccharomyces cerevisiae, Rad4 is involved in damage recognition during nucleotide excision repair (NER) and, in conjunction with Rad23, recruits other proteins to the site of damage. We identified a synthetic interaction upon UV exposure between Rad4 and Cdc20, a protein that modulates the activity of the anaphase promoting complex (APC/C), a multisubunit E3 ubiquitin ligase complex. The moderately UV sensitive Δrad4 strain became highly sensitive when cdc20-1 was present, and was rescued by overexpression of CDC20. The double mutant is also deficient in elicting RNR3-lacZ transcription upon exposure to UV irradiation or 4-NQO compared with the Δrad4 single mutant. We demonstrate that the Δrad4/cdc20-1 double mutant is defective in double strand break repair by way of a plasmid end-joining assay, indicating that Rad4 acts to ensure that damaged DNA is repaired via a Cdc20-mediated mechanism. This study is the first to present evidence that Cdc20 may play a role in the degradation of proteins involved in nucleotide excision repair.

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Growth Retardation, Early Death, and DNA Repair Defects in Mice Deficient for the Nucleotide Excision Repair Enzyme XPF

Molecular and Cellular Biology ◽

10.1128/mcb.24.3.1200-1205.2004 ◽

2004 ◽

Vol 24 (3) ◽

pp. 1200-1205 ◽

Cited By ~ 109

Author(s):

Ming Tian ◽

Reiko Shinkura ◽

Nobuhiko Shinkura ◽

Frederick W. Alt

Keyword(s):

Dna Repair ◽

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Excision Repair ◽

Genetic Defect ◽

Growth Defect ◽

Human Genetic Disease ◽

Nucleotide Excision ◽

Deficient Mice

ABSTRACT Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5′ to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes.

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Human exonuclease 1 connects nucleotide excision repair (NER) processing with checkpoint activation in response to UV irradiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1108547108 ◽

2011 ◽

Vol 108 (33) ◽

pp. 13647-13652 ◽

Cited By ~ 49

Author(s):

S. Sertic ◽

S. Pizzi ◽

R. Cloney ◽

A. R. Lehmann ◽

F. Marini ◽

...

Keyword(s):

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Excision Repair ◽

Checkpoint Activation ◽

Nucleotide Excision ◽

Exonuclease 1

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Rapid changes of nucleotide excision repair gene expression following UV-irradiation and cisplatin treatment of Dictyostelium discoideum

Nucleic Acids Research ◽

10.1093/nar/26.14.3397 ◽

1998 ◽

Vol 26 (14) ◽

pp. 3397-3403 ◽

Cited By ~ 15

Author(s):

S.-L. Yu ◽

S.-K. Lee ◽

H. Alexander ◽

S. Alexander

Keyword(s):

Gene Expression ◽

Dictyostelium Discoideum ◽

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Excision Repair ◽

Repair Gene ◽

Nucleotide Excision Repair Gene ◽

Nucleotide Excision ◽

Rapid Changes

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UV radiation-induced SUMOylation of DDB2 regulates nucleotide excision repair

Carcinogenesis ◽

10.1093/carcin/bgx076 ◽

2017 ◽

Vol 38 (10) ◽

pp. 976-985 ◽

Cited By ~ 7

Author(s):

Chunhua Han ◽

Ran Zhao ◽

John Kroger ◽

Jinshan He ◽

Gulzar Wani ◽

...

Keyword(s):

Dna Damage ◽

Nucleotide Excision Repair ◽

Uv Radiation ◽

Uv Irradiation ◽

Excision Repair ◽

26S Proteasome ◽

Cell Extracts ◽

Nucleotide Excision

Abstract Subunit 2 of DNA damage-binding protein complex (DDB2) is an early sensor of nucleotide excision repair (NER) pathway for eliminating DNA damage induced by UV radiation (UVR) and cisplatin treatments of mammalian cells. DDB2 is modified by ubiquitin and poly(ADP-ribose) (PAR) in response to UVR, and these modifications play a crucial role in regulating NER. Here, using immuno-analysis of irradiated cell extracts, we have identified multiple post-irradiation modifications of DDB2 protein. Interestingly, although the DNA lesions induced by both UVR and cisplatin are corrected by NER, only the UV irradiation, but not the cisplatin treatment, induces any discernable DDB2 modifications. We, for the first time, show that the appearance of UVR-induced DDB2 modifications depend on the binding of DDB2 to the damaged chromatin and the participation of functionally active 26S proteasome. The in vitro and in vivo analysis revealed that SUMO-1 conjugations comprise a significant portion of these UVR-induced DDB2 modifications. Mapping of SUMO-modified sites demonstrated that UVR-induced SUMOylation occurs on Lys-309 residue of DDB2 protein. Mutation of Lys-309 to Arg-309 diminished the DDB2 SUMOylation observable both in vitro and in vivo. Moreover, K309R mutated DDB2 lost its function of recruiting XPC to the DNA damage sites, as well as the ability to repair cyclobutane pyrimidine dimers following cellular UV irradiation. Taken together, our results indicate that DDB2 is modified by SUMOylation upon UV irradiation, and this post-translational modification plays an important role in the initial recognition and processing of UVR-induced DNA damage occurring within the context of chromatin.

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Mechanistic insights in transcription-coupled nucleotide excision repair of ribosomal DNA

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716581115 ◽

2018 ◽

Vol 115 (29) ◽

pp. E6770-E6779 ◽

Cited By ~ 6

Author(s):

Laurianne Daniel ◽

Elena Cerutti ◽

Lise-Marie Donnio ◽

Julie Nonnekens ◽

Christophe Carrat ◽

...

Keyword(s):

Rna Polymerase ◽

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Ribosomal Dna ◽

Excision Repair ◽

Rna Polymerase I ◽

Nucleotide Excision ◽

Polymerase I ◽

Uv Lesions ◽

Transcription Coupled Repair

Nucleotide excision repair (NER) guarantees genome integrity against UV light-induced DNA damage. After UV irradiation, cells have to cope with a general transcriptional block. To ensure UV lesions repair specifically on transcribed genes, NER is coupled with transcription in an extremely organized pathway known as transcription-coupled repair. In highly metabolic cells, more than 60% of total cellular transcription results from RNA polymerase I activity. Repair of the mammalian transcribed ribosomal DNA has been scarcely studied. UV lesions severely block RNA polymerase I activity and the full transcription-coupled repair machinery corrects damage on actively transcribed ribosomal DNAs. After UV irradiation, RNA polymerase I is more bound to the ribosomal DNA and both are displaced to the nucleolar periphery. Importantly, the reentry of RNA polymerase I and the ribosomal DNA is dependent on the presence of UV lesions on DNA and independent of transcription restart.

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A mutation-promotive role of nucleotide excision repair in cell cycle-arrested cell populations following UV irradiation

DNA Repair ◽

10.1016/j.dnarep.2009.10.007 ◽

2010 ◽

Vol 9 (1) ◽

pp. 96-100 ◽

Cited By ~ 6

Author(s):

Erich Heidenreich ◽

Herfried Eisler ◽

Theresia Lengheimer ◽

Petra Dorninger ◽

Ferdinand Steinboeck

Keyword(s):

Cell Cycle ◽

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Excision Repair ◽

Cell Populations ◽

Nucleotide Excision

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Deficiency in the Nuclease Activity of Xeroderma Pigmentosum G in Mice Leads to Hypersensitivity to UV Irradiation

Molecular and Cellular Biology ◽

10.1128/mcb.24.6.2237-2242.2004 ◽

2004 ◽

Vol 24 (6) ◽

pp. 2237-2242 ◽

Cited By ~ 36

Author(s):

Ming Tian ◽

David A. Jones ◽

Michele Smith ◽

Reiko Shinkura ◽

Frederick W. Alt

Keyword(s):

Nucleotide Excision Repair ◽

Uv Irradiation ◽

Xeroderma Pigmentosum ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Class Switch Recombination ◽

Nuclease Activity ◽

Class Switch ◽

Independent Functions ◽

Nucleotide Excision

ABSTRACT Xeroderma pigmentosum (XP) is a human disorder which is characterized by hypersensitivity to sunlight and elevated incidence of skin cancer. The disease is caused by mutations in genes that encode components of the nucleotide excision repair pathway. The gene product of XP complementation group G (XPG) is a structure-specific endonuclease which makes an incision 3′ to DNA photoproducts and other helix-distorting DNA adducts. In addition, the XPG protein has been implicated in transcription and repair of oxidative DNA damage. Moreover, XPG is capable of cleaving R loops in vitro, a potential intermediate during immunoglobulin heavy-chain class switch recombination. Due to its multiple functions, complete elimination of XPG in mice results in severe postnatal growth defects and premature death. To understand the contribution of the XPG nuclease activity to its function in vivo, we introduced a point mutation into the mouse XPG gene which inactivates the nuclease catalytic site but leaves the remainder of the protein intact. The XPG nuclease-deficient animals develop normally and exhibit no obvious defect in class switch recombination. However, the mutant mice are hypersensitive to UV irradiation. This phenotype suggests that the nuclease activity of XPG is required only for nucleotide excision repair and that other regions of the protein perform independent functions.

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