8 research outputs found
Asymmetric and Site-Selective [3 + 2]-Annulations for the Synthesis of High-Value Bicyclic Lactams
Asymmetric
and site-selective formal [3 + 2]-annulations of γ-alkyl-β,γ-unsaturated
γ-lactams with α,β-unsaturated aldehydes have been
developed. These organocatalysed transformations yield high value
enantioenriched bicyclic γ-lactams with up to four new stereocenters
(sometimes including a quarternary carbon). The overall transformation
starts from simple and readily accessible furans and oversees a rapid,
controlled, and dramatic enhancement in 3D complexity
HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence
Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome-wide in two primary cell lines. We integrated ChIP-seq and Hi-C with graph theory to uncover clustering of HMGB1-marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross-Linking and Immuno-Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA-binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP-relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell-autonomous and paracrine senescence
A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization
Oncogene-induced senescence (OIS) is an inherent and important tumor
suppressor mechanism. However, if not removed timely via immune
surveillance, senescent cells also have detrimental effects. Although
this has mostly been attributed to the senescence-associated secretory
phenotype (SASP) of these cells, we recently proposed that “escape”
from the senescent state is another unfavorable outcome. The mechanism
underlying this phenomenon remains elusive. Here, we exploit genomic and
functional data from a prototypical human epithelial cell model carrying
an inducible CDC6 oncogene to identify an early-acquired recurrent
chromosomal inversion that harbors a locus encoding the circadian
transcription factor BHLHE40. This inversion alone suffices for BHLHE40
activation upon CDC6 induction and driving cell cycle re-entry of
senescent cells, and malignant transformation. Ectopic overexpression of
BHLHE40 prevented induction of CDC6-triggered senescence. We provide
strong evidence in support of replication stress-induced genomic
instability being a causative factor underlying “escape” from
oncogene-induced senescence
HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types
Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, imaging, and in silico modeling of three distinct cells types entering senescence. Genes involved in DNA conformation maintenance are suppressed upon senescence entry across all cell types. We show that nuclear depletion of the abundant HMGB2 protein occurs early on the path to senescence and coincides with the dramatic spatial clustering of CTCF. Knocking down HMGB2 suffices for senescence-induced CTCF clustering and for loop reshuffling, while ectopically expressing HMGB2 rescues these effects. Our data suggest that HMGB2-mediated genomic reorganization constitutes a primer for the ensuing senescent program