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Unraveling the Role of JMJD1B in Genome Stability and the Malignancy of Melanomas.
Cruz, Perla; Peña-Lopez, Diego; Figueroa, Diego; Riobó, Isidora; Benedetti, Vincenzo; Saavedra, Francisco; Espinoza-Arratia, Claudia; Escobar, Thelma M; Lladser, Alvaro; Loyola, Alejandra.
Afiliação
  • Cruz P; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Peña-Lopez D; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Figueroa D; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Riobó I; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Benedetti V; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Saavedra F; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Espinoza-Arratia C; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
  • Escobar TM; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  • Lladser A; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
  • Loyola A; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile.
Int J Mol Sci ; 25(19)2024 Oct 04.
Article em En | MEDLINE | ID: mdl-39409021
ABSTRACT
Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in this pathway hinder chromatin assembly and contribute to genome instability. JMJD1B, a histone demethylase, not only regulates gene expression but also ensures a proper supply of histones H3 and H4 for the chromatin assembly. Reduced JMJD1B levels lead to the cytoplasmic accumulation of histones, causing defects in the chromatin assembly and resulting in DNA damage. To investigate the role of JMJD1B in regulating genome stability and the malignancy of melanoma tumors, we used a JMJD1B/KDM3B knockout in B16F10 mouse melanoma cells to perform tumorigenic and genome instability assays. Additionally, we analyzed the transcriptomic data of human cutaneous melanoma tumors. Our results show the enhanced tumorigenic properties of JMJD1B knockout melanoma cells both in vitro and in vivo. The γH2AX staining, Micrococcal Nuclease sensitivity, and comet assays demonstrated increased DNA damage and genome instability. The JMJD1B expression in human melanoma tumors correlates with a lower mutational burden and fewer oncogenic driver mutations. Our findings highlight JMJD1B's role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Dano ao DNA / Histonas / Instabilidade Genômica / Histona Desmetilases com o Domínio Jumonji / Melanoma Limite: Animals / Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Dano ao DNA / Histonas / Instabilidade Genômica / Histona Desmetilases com o Domínio Jumonji / Melanoma Limite: Animals / Humans Idioma: En Revista: Int J Mol Sci Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Chile País de publicação: Suíça