Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation

Vodenicharov, Momchil D.; Ghodgaonkar, Medini; Halappanavar, Sabina; Shah, Rashmi G.; Shah, Girish M.

doi:10.1242/jcs.01636

Cited by 63 publications

(68 citation statements)

References 59 publications

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“…PARP plays a role in the recognition of DNA damage, and it works synergistically with NER enzymes (46)(47)(48). Lysates derived from MyD88 2/2 (but not WT) PMs maintained functional PARP activity (ADP-ribosylate histones in vitro) (Fig.…”

Section: Discussionmentioning

confidence: 93%

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Harberts

Zhou

Fishelevich

et al. 2015

The Journal of Immunology

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UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer. We reported previously that the TLR4–MyD88 signaling axis is necessary for UV-induced apoptosis. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88-deficient (MyD88−/−) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88−/− mice compared with WT mice. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage–recognition molecule PARP, whereas PARP persisted in MyD88−/− and TLR4−/− APCs. Epidermal DNA from in vivo UV-irradiated MyD88−/− mice had an increased resolution rate of cyclobutane pyrimidine dimers. Both in vitro treatment of MyD88−/− APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage.

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Section: Discussionmentioning

confidence: 93%

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Harberts

Zhou

Fishelevich

et al. 2015

The Journal of Immunology

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“…Global and local UVC irradiation of cells has been reported (9). The repair kinetics assays for T-T and 6-4PP in cellular genomic DNA by flow cytometry and immunofluorescence microscopy and detection of NER proteins after local irradiation are detailed in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…We showed earlier that PARP-1 rapidly binds to UV-damaged DNA in vitro or in UV-irradiated cells, and it is activated to form PAR within seconds after irradiation at the site of DNA damage (9). Because DDB2, the early GG-NER protein, is also known to translocate very rapidly at the site of UV-damaged DNA (16), we examined whether DDB2 and PARP-1 interact with each other in the vicinity of UV-damaged chromatin using cellular fractions that represent chromatin-bound proteins (Chfraction) rather than the whole cell extract in coimmunoprecipitation (co-IP) studies (Fig.…”

Section: Parp Inhibitors Delaymentioning

confidence: 99%

Role of poly(ADP-ribose) polymerase-1 in the removal of UV-induced DNA lesions by nucleotide excision repair

Robu

Shah

Petitclerc

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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158

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Among the earliest responses of mammalian cells to DNA damage is catalytic activation of a nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Activated PARP-1 forms the polymers of ADPribose (pADPr or PAR) that posttranslationally modify its target proteins, such as PARP-1 and DNA repair-related proteins. Although this metabolism is known to be implicated in other repair pathways, here we show its role in the versatile nucleotide excision repair pathway (NER) that removes a variety of DNA damages including those induced by UV. We show that PARP inhibition or specific depletion of PARP-1 decreases the efficiency of removal of UV-induced DNA damage from human skin fibroblasts or mouse epidermis. Using NER-proficient and -deficient cells and in vitro PARP-1 assays, we show that damaged DNA-binding protein 2 (DDB2), a key lesion recognition protein of the global genomic subpathway of NER (GG-NER), associates with PARP-1 in the vicinity of UV-damaged chromatin, stimulates its catalytic activity, and is modified by pADPr. PARP inhibition abolishes UV-induced interaction of DDB2 with PARP-1 or xeroderma pigmentosum group C (XPC) and also decreases localization of XPC to UV-damaged DNA, which is a key step that leads to downstream events in GG-NER. Thus, PARP-1 collaborates with DDB2 to increase the efficiency of the lesion recognition step of GG-NER.M ammalian cells respond very rapidly to different types of DNA damage by activation of an abundant and ubiquitous nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). The activated PARP-1 uses NAD + to form polymers of ADP-ribose (pADPr or PAR) that modify PARP-1 itself and selected target proteins, such as histones and DNA repair proteins (1). This posttranslational modification, i.e., PARylation, has been implicated in cellular responses ranging from DNA repair to cell death. Among mammalian DNA repair pathways, PARP-1 has been implicated in base excision repair, homologous recombination, and nonhomologous end-joining pathways (2, 3), but we do not know its role in the most versatile nucleotide excision repair (NER) pathway that removes a wide variety of DNA lesions, including UV-induced thymine dimers (T-T) and other cyclobutane pyrimidine dimers (CPD), as well as 6-4 photoproducts (6-4PP) (4).The core mammalian NER pathway uses more than 30 proteins to recognize the damaged site on DNA, remove 24-to 32-nucleotide-long single-stranded DNA containing the lesion, fill the gap using the nondamaged strand as a template, and finally ligate the nick (4). There are two subpathways of NER: the transcription-coupled NER (TC-NER) removes lesions from the actively transcribed strands of the genes and the global genomic NER (GG-NER) repairs lesions from the entire genome. These two pathways differ in the initial step of lesion recognition: TC-NER is initiated when elongating RNA polymerase II stalls at the lesion, whereas GG-NER is initiated when the lesion is recognized in the chromatin context by DDB2 (XPE), which through its participation in the UV-DDB-E3 ligase complex ub...

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“…We have earlier shown that PARP-1 binds to UV-damaged large oligonucleotide in vitro or to chromatin fragments containing T-T lesions in vivo 11 . We also showed that PARP-1 and DDB2 associate with each other on the chromatin of UV-irradiated cells and that DDB2 stimulates catalytic activity of PARP-1 in the presence of UV-damaged DNA 7 .…”

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confidence: 99%

Characterization of the interactions of PARP-1 with UV-damaged DNA in vivo and in vitro

Purohit

Robu

Shah

et al. 2016

Sci Rep

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The existing methodologies for studying robust responses of poly (ADP-ribose) polymerase-1 (PARP-1) to DNA damage with strand breaks are often not suitable for examining its subtle responses to altered DNA without strand breaks, such as UV-damaged DNA. Here we describe two novel assays with which we characterized the interaction of PARP-1 with UV-damaged DNA in vivo and in vitro. Using an in situ fractionation technique to selectively remove free PARP-1 while retaining the DNA-bound PARP-1, we demonstrate a direct recruitment of the endogenous or exogenous PARP-1 to the UV-lesion site in vivo after local irradiation. In addition, using the model oligonucleotides with single UV lesion surrounded by multiple restriction enzyme sites, we demonstrate in vitro that DDB2 and PARP-1 can simultaneously bind to UV-damaged DNA and that PARP-1 casts a bilateral asymmetric footprint from −12 to +9 nucleotides on either side of the UV-lesion. These techniques will permit characterization of different roles of PARP-1 in the repair of UV-damaged DNA and also allow the study of normal housekeeping roles of PARP-1 with undamaged DNA.The abundance of poly (ADP-ribose) polymerase-1 (PARP-1) in mammalian cells and its rapid catalytic activation to form polymers of ADP-ribose (PAR) in the presence of various types of DNA damages with or without strand breaks has made it an ideal first responder at the lesion site to influence downstream events 1,2 . Apart from DNA damages, PARP-1 is also recruited to DNA during normal physiological processes such as transcription and chromatin remodeling 3 , which do not involve overt DNA damage but just altered DNA structures. While we know much more about how PARP-1 rapidly recognizes and binds to single or double strand breaks in DNA, we know very little about how PARP-1 interacts with DNA damages or altered DNA structures without strand breaks. The key reason is that the existing methodologies that readily identify interactions of PARP-1 with DNA strand breaks are not sufficiently sensitive to study the relatively weaker responses of PARP-1 to DNA damage without strand breaks. The response of PARP-1 to UVC-induced direct photolesions, such as cyclobutane pyrimidine dimers (CPD) that are formed without any DNA strand breaks exemplifies this problem.Recent studies from others and our team have shown the involvement of PARP-1 in the host cell reactivation 4 and specifically in the nucleotide excision repair (NER) of UV-damaged DNA through its interaction with early NER protein DDB2 [5][6][7] . Additional studies have shown that downstream NER proteins XPA 8,9 and XPC 10 are PARylated. Thus, PARP-1 possibly has multiple roles in NER, but we do not yet fully understand its interactions with UV-damaged DNA or other NER proteins due to two major challenges. The first challenge is that unlike for many NER proteins, the abundance of endogenous PARP-1 in the nucleus makes it nearly impossible to visualize its dynamics of recruitment to UV-damaged DNA in situ using conventional immunocytological methods. T...

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Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation

Cited by 63 publications

References 59 publications

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Ultraviolet Radiation Signaling through TLR4/MyD88 Constrains DNA Repair and Plays a Role in Cutaneous Immunosuppression

Role of poly(ADP-ribose) polymerase-1 in the removal of UV-induced DNA lesions by nucleotide excision repair

Characterization of the interactions of PARP-1 with UV-damaged DNA in vivo and in vitro

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