Centromere crisis: unraveling a novel link between mitotic errors, immune-sensors and senescence – CenCRISIS
Centromere Crisis: When Chromosome Errors Trigger Cellular Alarm Bells
Unraveling how centromere dysfunction and immune sensors shape genome stability and cellular aging
The project addresses a critical gap in our understanding of how cells detect and respond to chromosome mis-segregation. While aneuploidy is a hallmark of cancer, the cellular mechanisms that sense and react to these errors remain poorly defined. This project investigates how centromere dysfunction activates a senescence program via nuclear deformation and immune sensors like cGAS, and how DNA repair proteins like BRCA2 modulate this response. The ultimate goal is to uncover new pathways that maintain genome integrity and prevent malignant transformation.
Use of inducible degradation systems (AID) to deplete centromeric proteins (CENP-A, CENP-C) in human cells.
High-resolution imaging (SIM, TEM, AFM) to assess nuclear architecture and mechanics.
Biochemical and genomic assays (ChIP-qPCR, RNA-seq) to analyze chromatin changes and gene expression.
Functional assays to measure senescence, SADS formation, and p53/p21 activation.
Use of BRCA2 knockout and cGAS knockout models to dissect their roles in centromere integrity and immune signaling.
Chromosome mis-segregation leads to rapid activation of p53/p21, independent of DNA damage.
Nuclear deformation and softening are key triggers of this response, sensed by mTORC2 and ATR.
A novel mechanosensitive checkpoint at the nuclear envelope links chromosomal instability to cell cycle arrest.
This work opens new avenues for cancer therapy by targeting cells with chromosomal instability.
It suggests that nuclear mechanics and chromatin state are critical regulators of cellular fate.
Future research may explore how modulating cGAS or BRCA2 activity could influence aging and immune responses.
The findings could lead to new biomarkers for early detection of genome instability-related diseases.
Errors during cell division lead to karyotype imbalance (aneuploidy) and promote cellular inflammation and transformation. In response to aneuploidy, cells elicit a surveillance mechanism that stops proliferation and promotes senescence. Which are the molecular mechanisms that sense aneuploidy is still a matter of debate. Centromeres are key components in chromosome separation and contribute to prevent aneuploidy. They are also binding sites for DNA repair factors such as BRAC2 and the immune sensor cGAS. What is the link between these factors with centromeres and how they regulate centromere stability is unknown. Moreover, changes in centromere structure are associated with senescence onset but the molecular mechanisms that regulate such response remain unknown. In this proposal, we will i) reveal a novel causal link between centromere crisis, chromosome mis-segregation and cellular senescence and ii) determine the activity of intracellular immunity and BRAC2 in these processes. These will provide a transformative view on the molecular mechanisms behind the genesis of genome instability.
Project coordination
DANIELE FACHINETTI (Biologie cellulaire et Cancer, UMR144)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
DF Biologie cellulaire et Cancer, UMR144
NM IMMUNITE ET CANCER, U932
AC Intégrité du génome, ARN et cancer
Help of the ANR 575,316 euros
Beginning and duration of the scientific project:
February 2022
- 36 Months
