RESUMO
R-loops are three-stranded nucleic acid structures that are abundant and widespread across the genome and that have important physiological roles in many nuclear processes. Their accumulation is observed in cancers and neurodegenerative disorders. Recent studies have implicated a function for R-loops and G-quadruplex (G4) structures, which can form on the displaced single strand of R-loops, in three-dimensional genome organization in both physiological and pathological contexts. Here we discuss the interconnected functions of DNA:RNA hybrids and G4s within R-loops, their impact on DNA repair and gene regulatory networks, and their emerging roles in genome organization during development and disease.
Assuntos
Reparo do DNA , Quadruplex G , Estruturas R-Loop , Transcrição Gênica , Humanos , Estruturas R-Loop/genética , Animais , DNA/metabolismo , DNA/genética , DNA/química , Genoma/genética , Redes Reguladoras de Genes , RNA/metabolismo , RNA/genética , RNA/química , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.
Assuntos
Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Coesinas , Dano ao DNA , Replicação do DNA , Leucemia Mieloide Aguda , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Linhagem Celular Tumoral , Acetilação , Animais , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Camundongos , Cromatina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Apoptose , Proliferação de Células , Células HEK293RESUMO
Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility showed concomitant persistence. A two-color AP-1 reporter system showed that these memories are encoded in cis, constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.