RESUMEN
DNA repair through homologous recombination (HR) is of vital importance for maintaining genome stability and preventing tumorigenesis. RAD51 is the core component of HR, catalyzing the strand invasion and homology search. Here, we highlight recent findings on FIRRM and FIGNL1 as regulators of the dynamics of RAD51.
Asunto(s)
Recombinación Homóloga , Recombinasa Rad51 , Recombinación Homóloga/genética , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Humanos , Reparación del ADN/genética , Inestabilidad Genómica/genética , AnimalesRESUMEN
DNA lesions occur across the genome and constitute a threat to cell viability; however, damage at specific genomic loci has a relatively greater impact on overall genome stability. The ribosomal RNA gene repeats (rDNA) are emerging fragile sites. Recent progress in understanding how the rDNA damage response is organized has highlighted a key role of adaptor proteins. Here, we show that the scaffold tumor suppressor RASSF1A is recruited to rDNA breaks. RASSF1A recruitment to double-strand breaks is mediated by 53BP1 and depends on RASSF1A phosphorylation at Serine 131 by ATM kinase. Employing targeted rDNA damage, we uncover that RASSF1A recruitment promotes local ATM signaling. RASSF1A silencing, a common epigenetic event during malignant transformation, results in persistent breaks, rDNA copy number alterations and decreased cell viability. Overall, we identify a novel role for RASSF1A at rDNA break sites, provide mechanistic insight into how the DNA damage response is organized in a chromatin context, and provide further evidence for how silencing of the RASSF1A tumor suppressor contributes to genome instability.
Asunto(s)
Roturas del ADN de Doble Cadena , Proteínas de Unión al ADN , Proteínas Supresoras de Tumor/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Daño del ADN , Reparación del ADN , ADN Ribosómico/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Inestabilidad Genómica , Humanos , Fosforilación , Transducción de Señal/genética , Proteína 1 de Unión al Supresor Tumoral P53/genética , Proteína 1 de Unión al Supresor Tumoral P53/metabolismoRESUMEN
Human brain possesses a unique anatomy and physiology. For centuries, methodological barriers and ethical challenges in accessing human brain tissues have restricted researchers into using 2-D cell culture systems and model organisms as a tool for investigating the mechanisms underlying neurological disorders in humans. However, our understanding regarding the human brain development and diseases has been recently extended due to the generation of 3D brain organoids, grown from human stem cells or induced pluripotent stem cells (iPSCs). This system evolved into an attractive model of brain diseases as it recapitulates to a great extend the cellular organization and the microenvironment of a human brain. This chapter focuses on the application of brain organoids in modelling several neurodevelopmental and neurodegenerative diseases.
Asunto(s)
Encéfalo/patología , Enfermedades Neurodegenerativas/patología , Trastornos del Neurodesarrollo/patología , Organoides/patología , Humanos , Células Madre Pluripotentes Inducidas/patologíaRESUMEN
Joint DNA molecules are natural byproducts of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, compromising sister chromatid separation. The DNA translocase PICH (ERCC6L) has a central role in UFB resolution. A genome-wide loss-of-function screen is performed to identify the genetic context of PICH dependency. In addition to genes involved in DNA condensation, centromere stability, and DNA-damage repair, we identify FIGNL1-interacting regulator of recombination and mitosis (FIRRM), formerly known as C1orf112. We find that FIRRM interacts with and stabilizes the AAA+ ATPase FIGNL1. Inactivation of either FIRRM or FIGNL1 results in UFB formation, prolonged accumulation of RAD51 at nuclear foci, and impaired replication fork dynamics and consequently impairs genome maintenance. Combined, our data suggest that inactivation of FIRRM and FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in persistent DNA lesions and a dependency on PICH to preserve cell viability.
Asunto(s)
Mitosis , Proteínas , Proteínas/genética , Adenosina Trifosfatasas/metabolismo , ADN , Cromátides/metabolismo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Replicación del ADN/genética , Daño del ADNRESUMEN
Cell differentiation is a process that must be precisely regulated for the maintenance of tissue homeostasis. Differentiation towards a multiciliated cell fate is characterized by well-defined stages, where a transcriptional cascade is activated leading to the formation of multiple centrioles and cilia. Centrioles migrate and dock to the apical cell surface and, acting as basal bodies, give rise to multiple motile cilia. The concerted movement of cilia ensures directional fluid flow across epithelia and defects either in their number or structure can lead to disease phenotypes. Micro-RNAs (miRNAs; miRs) are small, non-coding RNA molecules that play an important role in post-transcriptional regulation of gene expression. miR-34b/c and miR-449a/b/c specifically function throughout the differentiation of multiciliated cells, fine-tuning the expression of many different centriole- and cilia-related genes. They strictly regulate the expression levels of genes that are required both for commitment towards the multiciliated cell fate (e.g. Notch) and for the establishment and maintenance of this fate by regulating the expression of transcription factors and structural components of the pathway. Herein we review miR-34 and miR-449 spatiotemporal regulation along with their roles during the different stages of multiciliogenesis.