RESUMO
Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
Assuntos
DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , DNA de Neoplasias/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Fatores de Transcrição/genética , Transcrição Gênica , Linhagem Celular Tumoral , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Dano ao DNA , DNA Helicases/metabolismo , Reparo do DNA , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , DNA Ribossômico/genética , Quadruplex G , Técnicas de Silenciamento de Genes , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Bitter melon or bitter gourd (Momordica charantia) is a common vegetable in Asia and it is distinctive for its bitter taste. As an ingredient in folk medicine, research from different laboratories in recent years supports its potential medicinal applications with anti-tumor, anti-diabetic, anti-HIV activities in both in vitro and animal studies. In this short review, we summarize herein the recent progress in the antitumor aspect of bitter melon with a focus on the underlying molecular mechanisms. Further mechanistic studies as well as clinical trials are necessary to further verify its medicinal applications.