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PMID:26773055
| Citation |
Poletto, M, Legrand, AJ, Fletcher, SC and Dianov, GL (2016) p53 coordinates base excision repair to prevent genomic instability. Nucleic Acids Res. 44:3165-75 |
|---|---|
| Abstract |
DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells. |
| Links |
PubMed PMC4838360 Online version:10.1093/nar/gkw015 |
| Keywords |
Cells, Cultured; DNA Breaks, Single-Stranded; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase/biosynthesis; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics; Down-Regulation; Genomic Instability; Humans; Sp1 Transcription Factor/metabolism; Tumor Suppressor Protein p53/metabolism |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0003697: single-stranded DNA binding |
ECO:0000314: |
F |
in Figure 3A, histogram displaying a ChIP analysis assessing Sp1 binding to APEX1 proximal promoter. The assay was carried out using TIG-1 cells transfected with either a control siRNA, a XRCC1 siRNA or a Sp1-targeting siRNA (as positive control for signal reduction). Results are expressed as mean fold enrichment over unspecific IgG relative to control siRNA ± SD of three independent experiments. |
complete | ||||
Notes
See also
References
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