Open AccessConstitutive High Expression of NOXA Sensitizes Human Embryonic Stem Cells for Rapid Cell Death
Author(s) -
Richa Basundra,
Sahil Kapoor,
Émilie Hollville,
Nazanin Kiapour,
Adriana Beltran Lopez,
Nicole Marie Melchiorre,
Mohanish Deshmukh
Publication year - 2022
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1093/stmcls/sxab008
Subject(s) - biology , embryonic stem cell , mcl1 , apoptosis , microbiology and biotechnology , dna damage , programmed cell death , stem cell , cell culture , dna , downregulation and upregulation , gene , genetics
Human embryonic stem (hES) cells are highly sensitive to apoptotic stimuli such as DNA damage, which allows for the rapid elimination of mutated cells during development. However, the mechanisms that maintain hES cells in the primed apoptotic state are not completely known. Key activators of apoptosis, the BH3-only proteins, are present at low levels in most cell types. In contrast, hES cells have constitutive high levels of the BH3-only protein, NOXA. We examined the importance of NOXA for enabling apoptosis in hES cells. hES cells deleted for NOXA showed remarkable protection against multiple apoptotic stimuli. NOXA was constitutively localized to the mitochondria, where it interacted with MCL1. Strikingly, inhibition of MCL1 in NOXA knockout cells was sufficient to sensitize these cells to DNA damage-induced cell death. Our study demonstrates that an essential function of constitutive high levels of NOXA in hES cells is to effectively antagonize MCL1 to permit rapid apoptosis.