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Published on: August 6, 2020
Nucleosome assembly proteins NAP1L1 and NAP1L4 modulate p53 acetylation to regulate cell fate
Toshiaki Tanaka1, Yasukazu Hozumi2, Alberto M Martelli3
1Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Abstract:
The p53 tumor suppressor regulates expression of genes involved in various stress responses. Upon genotoxic stress, p53 induces target genes regulating cell cycle arrest for survival or apoptosis. Nevertheless, detailed mechanisms of how p53 selectively regulates these opposing outcomes remain unclear. For this study, we investigated p53 regulatory mechanisms exerted by nucleosome assembly protein 1-like 1 (NAP1L1) and NAP1L4, both of which are identified as DGKζ-interacting proteins. Here we demonstrate that, under normal conditions, NAP1L1 knockdown decreases Lys320 acetylation of p53 with attenuated proarrest p21 expression, whereas NAP1L4 knockdown increases Lys320 acetylation with enhanced p21 expression. These conditions lead respectively to facilitation and suppression of cell growth. Under genotoxic stress conditions, NAP1L1 knockdown increases Lys382 acetylation with enhanced proapoptotic Bax levels, thereby facilitating cell death. By contrast, NAP1L4 knockdown decreases Lys382 acetylation with attenuated Bax levels, thereby suppressing apoptosis. These results suggest that NAP1L1 and NAP1L4 regulate cell fate by controlling the expression of p53-responsive proarrest and proapoptotic genes through selective modulation of p53 acetylation at specific sites during normal homeostasis and in stress-induced responses.
Insights
Nucleosome assembly proteins NAP1L1 and NAP1L4 regulate cell fate by modulating p53 acetylation. This controls expression of genes for cell cycle arrest or apoptosis, impacting cell growth and stress responses.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p53 tumor suppressor is crucial for cellular stress responses, regulating cell cycle arrest, survival, and apoptosis.
- The precise mechanisms by which p53 selectively induces opposing outcomes like survival or cell death remain incompletely understood.
Purpose of the Study:
- To investigate the roles of nucleosome assembly protein 1-like 1 (NAP1L1) and NAP1L4 in regulating p53 activity and downstream gene expression.
- To elucidate how these proteins modulate p53 acetylation at specific sites to control cellular fate.
Main Methods:
- Investigated the interaction of NAP1L1 and NAP1L4 with p53.
- Analyzed the effects of NAP1L1 and NAP1L4 knockdown on p53 acetylation at Lysine 320 and Lysine 382.
- Assessed the expression levels of p53 target genes, including p21 (proarrest) and Bax (proapoptotic).
Main Results:
- NAP1L1 knockdown decreased Lys320 acetylation and p21 expression, facilitating cell growth under normal conditions.
- NAP1L4 knockdown increased Lys320 acetylation and p21 expression, suppressing cell growth under normal conditions.
- Under genotoxic stress, NAP1L1 knockdown enhanced Lys382 acetylation and Bax levels, promoting apoptosis.
- Conversely, NAP1L4 knockdown decreased Lys382 acetylation and Bax levels, suppressing apoptosis.
Conclusions:
- NAP1L1 and NAP1L4 differentially regulate p53 acetylation at specific lysine residues (Lys320 and Lys382).
- These proteins control the balance between cell cycle arrest and apoptosis by modulating p53-responsive gene expression.
- NAP1L1 and NAP1L4 act as key regulators of cell fate decisions in response to normal homeostasis and genotoxic stress.
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