Journal
EMBO JOURNAL
Volume 28, Issue 20, Pages 3207-3215Publisher
WILEY
DOI: 10.1038/emboj.2009.243
Keywords
ARF; base excision repair; DNA polymerase beta; Mule; ubiquitylation
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Funding
- Medical Research Council
- Cancer Research UK
- NIHR Biomedical Research Centre, Oxford
- MRC [G0700730, G0501068] Funding Source: UKRI
- Cancer Research UK [8971] Funding Source: researchfish
- Medical Research Council [G0700730, G0501068] Funding Source: researchfish
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Base excision repair (BER) is the major cellular pathway involved in removal of endogenous/spontaneous DNA lesions. Here, we study the mechanism that controls the steady-state levels of BER enzymes in human cells. By fractionating human cell extract, we purified the E3 ubiquitin ligase Mule (ARF-BP1/HectH9) as an enzyme that can ubiquitylate DNA polymerase beta (Pol beta), the major BER DNA polymerase. We identified lysines 41, 61 and 81 as the major sites of modification and show that replacement of these lysines to arginines leads to increased protein stability. We further show that the cellular levels of Pol beta and its ubiquitylated derivative are modulated by Mule and ARF and siRNA knockdown of Mule leads to accumulation of Pol beta and increased DNA repair. Our findings provide a novel mechanism regulating steady-state levels of BER proteins. The EMBO Journal (2009) 28, 3207-3215. doi:10.1038/emboj.2009.243; Published online 27 August 2009
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