Author Correction: Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability.
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ABSTRACT:
SUBMITTER: Galanos P
PROVIDER: S-EPMC9052693 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
Publications
Author Correction: Mutational signatures reveal the role of RAD52 in p53-independent p21-driven genomic instability.
Galanos Panagiotis P Pappas George G Polyzos Alexander A Kotsinas Athanassios A Svolaki Ioanna I Giakoumakis Nickolaos N NN Glytsou Christina C Pateras Ioannis S IS Swain Umakanta U Souliotis Vassilis L VL Georgakilas Alexandros G AG Geacintov Nicholas N Scorrano Luca L Lukas Claudia C Lukas Jiri J Livneh Zvi Z Lygerou Zoi Z Chowdhury Dipanjan D Sørensen Claus Storgaard CS Bartek Jiri J Gorgoulis Vassilis G VG
Genome biology 20220428 1
Similar Datasets
Project description:BackgroundGenomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1, showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery.ResultsWe now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities. Consequently, fewer single nucleotide substitutions (SNSs) occur, while formation of highly deleterious DNA double-strand breaks (DSBs) is enhanced, crafting a characteristic mutational signature landscape. Guided by the mutational signatures formed, we find that the DSBs are repaired by Rad52-dependent break-induced replication (BIR) and single-strand annealing (SSA) repair pathways. Conversely, the error-free synthesis-dependent strand annealing (SDSA) repair route is deficient. Surprisingly, Rad52 is activated transcriptionally in an E2F1-dependent manner, rather than post-translationally as is common for DNA repair factor activation.ConclusionsOur results signify the importance of mutational signatures as guides to disclose the repair history leading to genomic instability. We unveil how chronic p21WAF1/Cip1 expression rewires the repair process and identifies Rad52 as a source of genomic instability and a candidate therapeutic target.
| S-EPMC5857109 | biostudies-literature
Project description:The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
| S-EPMC6535144 | biostudies-literature
Project description:P53 independent P21 expression deregulates replication licensing , leading to genomic instability
2016-05-17 | PXD004140 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-05-24 | GSE81754 | GEO
Project description:MELK play critical roles in human carcinogenesis through activation of cell proliferation, inhibition of apoptosis and maintenance of stemness. Therefore, MELK is a promising therapeutic target for a wide range of cancers. Although p21 is a well-known p53-downstream gene, we found that treatment with a potent MELK inhibitor, OTS167, could induce p21 protein expression in cancer cell lines harboring loss-of-function TP53 mutations. We also confirmed that MELK knockdown by siRNA induced the p21 expression in p53-deficient cancer cell lines and caused the cell cycle arrest at G1 phase. Further analysis indicated that FOXO1 and FOXO3, two known transcriptional regulators of p21, were phosphorylated by MELK and thus be involved in the induction of p21 after MELK inhibition. Collectively, our herein findings suggest that MELK inhibition may be effective for human cancers even if TP53 is mutated.
| S-EPMC5601624 | biostudies-literature
Project description:The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that, through a so-far obscure mechanism, p21 could also be oncogenic. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery, an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
2016-05-24 | GSE81753 | GEO
Project description:The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that, through a so-far obscure mechanism, p21 could also be oncogenic. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemo-resistance. Mechanistically, sustained p21-accumulation inhibited mainly the CRL4CDT2 ubiquitin-ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery, an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
2016-05-24 | GSE81752 | GEO
Project description: Not available
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Project description: Not available
| S-EPMC7864967 | biostudies-literature
Project description:Traditionally, the p21 protein has been viewed as limiting cancer progression and promoting aging. In contrast, there are reports that p21 can enhance cancer survival and limit tissue damage, depending on the tissue of origin and type of stressor involved. Here, we provide evidence to support these latter two roles of p21 by exploring its ability to regulate ferroptosis. Ferroptosis is a form of cell death that is associated with certain degenerative diseases, some of which are aging-related. Our results reveal a correlation between p21 protein levels in cell lines that are resistant to ferroptosis (p21 high) versus cell lines that are sensitive and easily undergo ferroptosis (p21 low). We also show that p21 levels themselves are differentially regulated in response to ferroptosis in a p53-independent manner. Further, experimentally altering the abundance of p21 protein inverts the ferroptosis-sensitivity of both resistant and sensitive human cancer cell lines. Our data also indicate that the interaction of p21 with CDKs is crucial for its ability to restrict the progression of ferroptosis. While this study was performed in cancer cell lines, our results support the potential of p21 to aid in maintenance of healthy tissues by blocking the damage incurred due to ferroptosis.
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