RESUMO
Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.
Assuntos
Pontos de Checagem do Ciclo Celular , Senescência Celular , Fator de Transcrição E2F7/metabolismo , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Fator de Transcrição E2F7/genética , Humanos , Camundongos , Camundongos Knockout , Mitose/genética , Proteína do Retinoblastoma/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
The histone variant macroH2A generally associates with transcriptionally inert chromatin; however, the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase ATRX (α-thalassemia/MR, X-linked) as a novel macroH2A-interacting protein. Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A's chromatin association. In human erythroleukemic cells deficient for ATRX, macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of α-globin expression. Collectively, our results implicate deregulation of macroH2A's distribution as a contributing factor to the α-thalassemia phenotype of ATRX syndrome.
Assuntos
Cromatina/metabolismo , DNA Helicases/metabolismo , Regulação da Expressão Gênica , Histonas/metabolismo , Proteínas Nucleares/metabolismo , alfa-Globinas/genética , alfa-Globinas/metabolismo , DNA Helicases/genética , Células Eritroides/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Células K562 , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Proteínas Nucleares/genética , Telômero/metabolismo , Proteína Nuclear Ligada ao X , Talassemia alfa/patologiaRESUMO
Conditional control of RNA structure and function has emerged as an effective toolkit. Here, a strategy based on a one-step introduction of diacylation linkers and azide groups on the 2'-OH of RNA is advance. Selected from eight phosphine reagents, it is found that 2-(diphenylphosphino)ethylamine has excellent performance in reducing azides via a Staudinger reduction to obtain the original RNA. It is demonstrated that the enzymatic activities of Cas13 and Cas9 can be regulated by chemically modified guide RNAs, and further achieved ligand-induced gene editing in living cells by a controllable CRISPR/Cas9 system.
Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Sistemas CRISPR-Cas/genética , RNA Guia de Sistemas CRISPR-CasRESUMO
To validate the JAMR F1701T (arm type) blood pressure (BP) monitor according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018). A total of 90 subjects (male 60 and female 30) were recruited to fulfill the criteria of the AAMI/ESH/ISO Universal Standard (the number, gender, age, limber size, and BP distribution), and sequential measurements of BP, including both SBP and DBP were obtained using the test device and the standard mercury sphygmomanometer. A total of 270 sets of comparison data (three sets of each subject) were obtained and analyzed. According to the validation criterion 1 of ISO 81060-2:2018, the mean ± SD of the differences between the JAMR F1701T and mercury sphygmomanometer BP (systolic/diastolic) readings was 2.06 ± 6.83/-4.84 ± 5.23 mmHg. For criterion 2, the SD of the averaged BP (systolic/diastolic) differences between the JAMR F1701 and reference BP (systolic/diastolic) per participant was 5.62/4.39 mmHg (the requirement was ≤6.43/5.01 mmHg by calculation). The JAMR F1701T met all the requirements of the ISO 81060-2:2018, and can be recommended for clinical and self/home use.