Xeroderma pigmentosum group C protein interacts with histones: regulation by acetylated states of histone H3

Kakumu, Erina; Nakanishi, Seiya; Shiratori, Hiromi; Kato, Aki; Kobayashi, Wataru; Machida, Shuichi; Yasuda, Takeshi; Adachi, Naoko; Saito, Naoaki; Ikura, Tsuyoshi; Kurumizaka, Hitoshi; Kimurâ, Hiroshi; Yokoi, Masayuki; Sakai, Wataru; Sugasawa, Kaoru

doi:10.1111/gtc.12479

Cited by 23 publications

(26 citation statements)

References 83 publications

(85 reference statements)

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“…A recent report demonstrated a direct interaction between histone and XPC, through which histone deacetylation modulates the localization and functions of XPC in the process of DNA damage recognition for NER 48 . Here we show that DOT1L/H3K79 methylation also plays the crucial role on the regulation of XPC recognition of DNA lesion and modulates the interaction between XPC and histones.…”

Section: Resultsmentioning

confidence: 99%

The protective role of DOT1L in UV-induced melanomagenesis

et al. 2018

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The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.

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Section: Resultsmentioning

confidence: 99%

The protective role of DOT1L in UV-induced melanomagenesis

et al. 2018

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“…A particular difference is that XP patients show a high frequency of skin cancer, while TTD and CS patients have a low incidence of tumors; also, the CS syndrome includes developmental and neurological abnormalities [ 21 ]. In view of the complex genomics of these several syndromes, it is not surprising that there are conflicting reports on the effects of HDAC inhibition on the efficiency of NER among these different but related pathologies [ 23 – 27 ]. In the context of this present study, it is primarily of interest that PBZ shows considerable concurrence with classical HDAC inhibitors in regard to gene enrichment scores for UVC-related gene signatures.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor activity of phenoxybenzamine and its inhibition of histone deacetylases

Inchiosa

2018

PLoS ONE

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The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several “off label” indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact that certain types of neuropathic pain, in particular complex regional pain syndrome, demonstrate a proliferative nature, with the capacity to spread from an injured limb, for example, to a non-injured limb and perhaps to essentially the entire body. Sensory neuronal sprouting in the spinal cord has been observed under conditions where there is a high sensory input from painful stimuli. Searches of gene expression signatures in the BroadBuild02 Molecular Signature Database using their connectivity map software suggested that phenoxybenzamine may have histone deacetylase inhibitory activity. Studies by others have reported inhibitory effects of phenoxybenzamine on growth, invasion and migration of human tumor cell cultures and, in one study, inhibition of tumor expansion in animal experiments. Inhibitory effects on human tumor cell cultures are also reported in the present study. Phenoxybenzamine was also found to have histone deacetylase inhibitory activity; histone deacetylase isoforms 5, 6, and 9 were the most sensitive to inhibition by phenoxybenzamine. The importance of elevated levels of these isoforms as biomarkers of poor prognosis in human malignant disease, and the recognized suppression of tumor growth that may accrue from their inhibition, opens consideration of possible translation of phenoxybenzamine to new clinical applications. This might be facilitated by the fact that phenoxybenzamine is already an approved drug entity. There appears to be no previous report of the activity of phenoxybenzamine as a histone deacetylase inhibitor.

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“…Because 6–4PPs are shown to be generated by UV irradiation in chromatin in a relatively random manner [46], this fact strongly suggests existence of unprecedented molecular mechanisms that enable alteration of chromatin structures prior to lesion detection by XPC. We have recently reported that XPC physically interacts with histone H3 and this interaction is negatively regulated by acetylation of the histone protein [47]. Moreover, in living cells, inhibition of histone deacetylases compromises GG-NER, and deacetylation of histones appears to occur around sites with UV-induced DNA damage.…”

Section: Uv-ddb and Chromatin Structuresmentioning

confidence: 99%

Mechanism and regulation of DNA damage recognition in nucleotide excision repair

et al. 2019

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Nucleotide excision repair (NER) is a versatile DNA repair pathway, which can remove an extremely broad range of base lesions from the genome. In mammalian global genomic NER, the XPC protein complex initiates the repair reaction by recognizing sites of DNA damage, and this depends on detection of disrupted/destabilized base pairs within the DNA duplex. A model has been proposed that XPC first interacts with unpaired bases and then the XPD ATPase/helicase in concert with XPA verifies the presence of a relevant lesion by scanning a DNA strand in 5′-3′ direction. Such multi-step strategy for damage recognition would contribute to achieve both versatility and accuracy of the NER system at substantially high levels. In addition, recognition of ultraviolet light (UV)-induced DNA photolesions is facilitated by the UV-damaged DNA-binding protein complex (UV-DDB), which not only promotes recruitment of XPC to the damage sites, but also may contribute to remodeling of chromatin structures such that the DNA lesions gain access to XPC and the following repair proteins. Even in the absence of UV-DDB, however, certain types of histone modifications and/or chromatin remodeling could occur, which eventually enable XPC to find sites with DNA lesions. Exploration of novel factors involved in regulation of the DNA damage recognition process is now ongoing.

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Xeroderma pigmentosum group C protein interacts with histones: regulation by acetylated states of histone H3

Cited by 23 publications

References 83 publications

The protective role of DOT1L in UV-induced melanomagenesis

The protective role of DOT1L in UV-induced melanomagenesis

Anti-tumor activity of phenoxybenzamine and its inhibition of histone deacetylases

Mechanism and regulation of DNA damage recognition in nucleotide excision repair

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