Cited by 108DNA Repair MechanismsCancer-related Molecular PathwaysCell death mechanisms and regulation

DDB2 decides cell fate following DNA damage

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Stoyanova, Tanya, Roy, Nilotpal, Kopanja, Dragana, Bagchi, Srilata, Raychaudhuri, Pradip·2009·Proceedings of the National Academy of Sciences

Abstract

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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Crossref · 10.1073/pnas.0812254106

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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
Published
2009-06-30
Volume
106
Issue
26
Pages
10690-10695
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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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