DNA Polymerase Eta Stabilizes Mutant p53 Protein to Increase Tumor Cell Growth
- 1Comparative Oncology Laboratory, Weill School of Veterinary Medicine and School of Medicine, University of California, Davis, CA 95616, USA
Abstract
DNA polymerase eta (PolH) is a specialized translesion synthesis DNA polymerase that enables replication across damaged DNA and contributes to cellular tolerance of genotoxic stress. Although PolH has been implicated in chemoresistance, its role in oncogenic signaling remains poorly understood. Here, we identify an unexpected role of PolH in tumor cell growth via mutant p53. We found that overexpression of PolH increases the level of mutant p53 protein. By contrast, knockdown or knockout of PolH inhibits mutant p53 expression by decreasing the half-life of mutant p53 protein. We also found that knockdown or knockout of PolH leads to increased expression of SKP2. As a key E3 ubiquitin ligase component of the SCF complex, we showed that overexpression of SKP2 decreases whereas knockdown of SKP2 increases mutant p53 expression. Moreover, we showed that knockdown of SKP2 abrogates the ability of PolH to regulate mutant p53 expression. To determine the role of SKP2 in mediating mutant p53 proteasome degradation, we showed that SKP2 interacts with mutant p53(R237H). We also found that wild-type but not F-box-deleted SKP2 poly-ubiquitinates mutant p53(R273H). Importantly, we showed that tumor sphere formation is inhibited by knockdown or knockout of PolH, which is further inhibited by knockdown of mutant p53, supporting a cooperative role for PolH and mutant p53 in tumor cell growth. Collectively, these observations indicate that PolH is a previously unrecognized regulator of mutant p53 via SKP2 and that the PolH–mutant p53 pathway can be explored as a therapeutic strategy for mutant p53-driven cancers.
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BibTeX
@article{zhang2026polymerase,
title = {{DNA Polymerase Eta Stabilizes Mutant p53 Protein to Increase Tumor Cell Growth}},
author = {Jin Zhang and Yang Shi and Xinbin Chen},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201881},
url = {https://www.mdpi.com/2073-4409/15/20/1881},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - DNA Polymerase Eta Stabilizes Mutant p53 Protein to Increase Tumor Cell Growth
AU - Jin Zhang
AU - Yang Shi
AU - Xinbin Chen
PY - 2026
DA - 2026/10/15
JO - Cells
DO - 10.3390/cells15201881
UR - https://www.mdpi.com/2073-4409/15/20/1881
AB - DNA polymerase eta (PolH) is a specialized translesion synthesis DNA polymerase that enables replication across damaged DNA and contributes to cellular tolerance of genotoxic stress. Although PolH has been implicated in chemoresistance, its role in oncogenic signaling remains poorly understood. Here, we identify an unexpected role of PolH in tumor cell growth via mutant p53. We found that overexpression of PolH increases the level of mutant p53 protein. By contrast, knockdown or knockout of PolH inhibits mutant p53 expression by decreasing the half-life of mutant p53 protein. We also found that knockdown or knockout of PolH leads to increased expression of SKP2. As a key E3 ubiquitin ligase component of the SCF complex, we showed that overexpression of SKP2 decreases whereas knockdown of SKP2 increases mutant p53 expression. Moreover, we showed that knockdown of SKP2 abrogates the ability of PolH to regulate mutant p53 expression. To determine the role of SKP2 in mediating mutant p53 proteasome degradation, we showed that SKP2 interacts with mutant p53(R237H). We also found that wild-type but not F-box-deleted SKP2 poly-ubiquitinates mutant p53(R273H). Importantly, we showed that tumor sphere formation is inhibited by knockdown or knockout of PolH, which is further inhibited by knockdown of mutant p53, supporting a cooperative role for PolH and mutant p53 in tumor cell growth. Collectively, these observations indicate that PolH is a previously unrecognized regulator of mutant p53 via SKP2 and that the PolH–mutant p53 pathway can be explored as a therapeutic strategy for mutant p53-driven cancers.
SN - 2073-4409
ER -