Senescence is a form of irreversible growth arrest, induced in response to cell
stresses such as DNA damage, telomere erosion, and oncogenic shock.
Senescent cells are associated with many different pathologies.
Understanding the regulatory mechanisms controlling the induction of
senescence can facilitate the study of associated diseases, particularly cancer
and age-related diseases. Epigenetic pathways play a crucial role in
regulating the induction and maintenance of senescence, and we need a
better understanding of the epigenetic mechanisms controlling senescence.
In a genetic screen for epigenetic factors controlling senescence, our lab
identified ENY2- a highly conserved protein found in two different complexes:
SAGA, a histone-modifying complex, and TREX2, involved in mRNA export.
This investigation aimed to characterise the mechanism through which ENY2
regulates senescence. shRNAs knocking down ENY2 prevented the growth
arrest observed in IMR90 ER: RAS, a model of oncogene-induced
senescence. Knockdown of multiple components of SAGA, but not the TREX2
complex, also blunted the senescence growth arrest. In accordance, ENY2
was thought to control senescence through the SAGA complex at the level of
histone modification. On ENY2 knockdown, there were profound changes in
global H2BUb levels and a reduction in SAHF formation.
Understanding that these global chromatin changes could affect transcription,
I explored the impact of ENY2 knockdown on gene expression during entry to
senescence. RNA-seq showed upregulation of key transcripts involved in the
G1 to S transition in senescent cells depleted of ENY2. These cells escaped
senescence growth arrest and displayed increased BrdU incorporation and
Rb phosphorylation, while other aspects of the senescence phenotype such
as the SASP and persistent DDR remained unchanged. Further investigation
will elucidate the precise mechanism by which ENY2 controls senescence.