Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation

Park, Jeong-Min; Kang, Tae-Hong

doi:10.3390/ijms17111840

Cited by 33 publications

(39 citation statements)

References 109 publications

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“…Because NER is responsible for physically removing UV-induced DNA lesions, our results offer mechanistic insight into the prior observation that β-HPV E6 delays repair of UV photo-products [29,36]. Specifically, β-HPV E6 reduces the ATR-dependent phosphorylation required for XPA stabilization and NER function [37,38]. β-HPV E6 also attenuates stabilization of POLη, the TLS polymerase most relevant for bypassing UV lesions [39,40].…”

Section: Introductionsupporting

confidence: 56%

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Snow

Murthy

Dacus

et al. 2019

Preprint

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Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they are manipulating their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 protein from β-HPV (β-HPV E6) decreases the abundance of two essential UV-repair kinases (ATM and ATR). Since β-HPV E6 reduces their availability, the impact on downstream signaling events has been uncertain. We demonstrate that β-HPV E6 decreases ATM and ATR activation. This inhibition extended to XPA, an ATR target necessary for UV repair, lowering both its phosphorylation and accumulation. β-HPV E6 hinders POLη phosphorylation and foci formation, critical steps in translesion synthesis. ATM’s phosphorylation of BRCA1 is also attenuated by β-HPV E6. However, β-HPV E6’s hindrance of ATM/ATR signaling during UV-associated cell cycle arrest was incomplete. While there was less phosphorylation of immediate downstream targets (CHK1), events further down the cascade were not decreased. These observations are consistent with β-HPV infections making UV radiation more deleterious and support the proposed role of β-HPV in early stages of non-melanoma skin cancer development.

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Section: Introductionsupporting

confidence: 56%

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Snow

Murthy

Dacus

et al. 2019

Preprint

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“…The effects of α-MSH or End-1 were dependent on ATR and ATM, as treatment with VE281 reduced the effects of α-MSH or End-1 on cytoplasmic and chromatin-bound XPA, and treatment with KU60019 inhibited their effects on chromatin-bound XPA (Figure 3b,c). Our results are consistent with previous reports that XPA localizes predominantly in the cytoplasm, and that upon UV exposure, it is imported to the nucleus in an ATR-dependent manner (Park & Kang, 2016;Shell et al, 2009).…”

Section: Endothelin-1 and α-Msh Promote Dna Damage Verificationsupporting

confidence: 93%

Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

Swope

Starner

Rauck

et al. 2019

Pigment Cell Melanoma Res

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Human melanocyte homeostasis is sustained by paracrine factors that reduce the genotoxic effects of ultraviolet radiation (UV), the major etiological factor for melanoma. The keratinocyte‐derived endothelin‐1 (End‐1) and α‐melanocyte‐stimulating hormone (α‐MSH) regulate human melanocyte function, proliferation and survival, and enhance repair of UV‐induced DNA photoproducts by binding to the Gq‐ and Gi‐protein‐coupled endothelin B receptor (EDNRB), and the Gs‐protein‐coupled melanocortin 1 receptor (MC1R), respectively. We hereby report that End‐1 and α‐MSH regulate common effectors of the DNA damage response to UV, despite distinct signaling pathways. Both factors activate the two DNA damage sensors ataxia telangiectasia and Rad3‐related and ataxia telangiectasia mutated, enhance DNA damage recognition by reducing soluble nuclear and chromatin‐bound DNA damage binding protein 2, and increase total and chromatin‐bound xeroderma pigmentosum (XP) C. Additionally, α‐MSH and End‐1 increase total levels and chromatin localization of the damage verification protein XPA, and the levels of γH2AX, which facilitates recruitment of DNA repair proteins to DNA lesions. Activation of EDNRB compensates for MC1R loss of function, thereby reducing the risk of malignant transformation of these vulnerable melanocytes. Therefore, MC1R and EDNRB signaling pathways represent redundant mechanisms that inhibit the genotoxic effects of UV and melanomagenesis.

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“…We test this hypothesis with a combination of in silico and in vitro analyses, specifically focusing on phosphorylation events that facilitate cell cycle regulation, nucleotide excision repair (NER), and translesion synthesis (TLS). NER is responsible for physically removing UV-induced DNA lesions and it has been shown that an essential protein, XPA, is stabilized by ATR phosphorylation [37,38]. The TLS pathway helps bypass UV lesions primarily through the TLS polymerase, POLη, which is regulated by ATR and p53 [39,40].…”

Section: Introductionmentioning

confidence: 99%

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

et al. 2019

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Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they manipulate their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 protein from β-genus HPV (β-HPV E6) decreases the abundance of two essential UV-repair kinases (ATM and ATR). Although β-HPV E6 reduces their availability, the impact on downstream signaling events is unclear. We demonstrate that β-HPV E6 decreases ATM and ATR activation. This inhibition extended to XPA, an ATR target necessary for UV repair, lowering both its phosphorylation and accumulation. β-HPV E6 also hindered POLη accumulation and foci formation, critical steps in translesion synthesis. ATM’s phosphorylation of BRCA1 is also attenuated by β-HPV E6. While there was a striking decrease in phosphorylation of direct ATM/ATR targets, events further down the cascade were not reduced. In summary, despite being incomplete, β-HPV 8E6’s hindrance of ATM/ATR has functional consequences.

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Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation

Cited by 33 publications

References 109 publications

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

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Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation

Cited by 33 publications

References 109 publications

&beta;-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

&beta;-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Endothelin‐1 and α‐melanocortin have redundant effects on global genome repair in UV‐irradiated human melanocytes despite distinct signaling pathways

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

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β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage