DDB2 decides cell fate following DNA damage
Open accessAbstract
The xeroderma pigmentosum complementation group E (XP-E) gene product damaged-DNA binding protein 2 (DDB2) plays important roles in nucleotide excision repair (NER). Previously, we showed that DDB2 participates in NER by regulating the level of p21(Waf1/Cip1). Here we show that the p21(Waf1/Cip1) -regulatory function of DDB2 plays a central role in defining the response (apoptosis or arrest) to DNA damage. The DDB2-deficient cells are resistant to apoptosis in response to a variety of DNA-damaging agents, despite activation of p53 and the pro-apoptotic genes. Instead, these cells undergo cell cycle arrest. Also, the DDB2-deficient cells are resistant to E2F1-induced apoptosis. The resistance to apoptosis of the DDB2-deficient cells is caused by an increased accumulation of p21(Waf1/Cip1) after DNA damage. We provide evidence that DDB2 targets p21(Waf1/Cip1) for proteolysis. The resistance to apoptosis in DDB2-deficient cells also involves Mdm2 in a manner that is distinct from the p53-regulatory activity of Mdm2. Our results provide evidence for a new regulatory loop involving the NER protein DDB2, Mdm2, and p21(Waf1/Cip1) that is critical in deciding cell fate (apoptosis or arrest) upon DNA damage.
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DDB2 is a cellular fate determinant after DNA damage, regulating between cell cycle arrest when DDB2 is present versus when DDB2 is absent, as shown in WT and DDB2−/− MEFs.
“DDB2 was found to regulate between cell cycle arrest with DDB2 present versus cell cycle arrest when DDB2 is absent through experiments performed in WT and DDB2−/− MEFs [50,51].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [50]
DDB2 regulates the cell cycle arrest mediator p21Waf1/Cip1 to induce apoptosis.
“Interestingly, they also found that the cell cycle arrest mediator p21Waf1/Cip1 is regulated by DDB2 to induce apoptosis.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [50]
Silencing Mdm2 in addition to DDB2 reverses the effect of DDB2 silencing on apoptosis in the presence of DNA damage.
“This effect was reversed with silencing Mdm2 in addition to DDB2 in the presence of DNA damage.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [50]
Mdm2 inhibits apoptosis in conjunction with UV, cisplatin and doxorubicin in HeLa cells when DDB2 is silenced.
“Mdm2 inhibited apoptosis in conjunction with UV, cisplatin and doxorubicin in HeLa cells when DDB2 was silenced [50].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [50]
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- Authors
- Stoyanova, T., Roy, N., Kopanja, D., Bagchi, S., & Raychaudhuri, P.
- Affiliations
- University of Illinois Chicago (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-06-30
- Volume
- 106
- Issue
- 26
- Pages
- 10690-10695
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2705559
- OpenAlex
- W2034903905
- Cited by
- 108
- References
- 40
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 18 · 2021: 2 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 7 · 2013: 12 · 2012: 7
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Illinois at Urbana-Champaign
- National Institute on Aging (R01AG024138, AG024138)
- National Cancer Institute (R01CA077637, CA77637)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- DDB2, nucleotide excision repair, p21, apoptosis, cell cycle arrest, MDM2, p53, E2F1, DNA damage response, proteolysis, cell fate determination
- MeSH terms
- Animals, Antineoplastic Agents, Cell Cycle, Cells, Cultured, Cisplatin, DNA Damage, DNA Repair, DNA-Binding Proteins, Fibroblasts, Flow Cytometry, HeLa Cells, Humans, Ultraviolet Rays, Blotting, Western, Aclarubicin, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2
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