Abstract
Limiting the levels of homologous recombination (HR) that occur at sites of DNA damage is a major role of BLM helicase. However, very little is known about the mechanisms dictating its relocalization to these sites. Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80. Furthermore, we show that this mechanism of BLM relocalization is essential for BLM's ability to suppress excessive/uncontrolled HR at stalled replication forks. Unexpectedly, we also uncovered a requirement for RNF8-dependent ubiquitylation of BLM and PML for maintaining the integrity of PML-associated nuclear bodies and as a consequence the localization of BLM to these structures. Lastly, we identified a novel role for RAP80 in preventing proteasomal degradation of BLM in unstressed cells. Taken together, these data highlight an important biochemical link between the UbS-DDR and BLM-dependent pathways involved in maintaining genome stability.
Original language | English |
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Pages (from-to) | 1778-92 |
Number of pages | 15 |
Journal | The EMBO journal |
Volume | 32 |
Issue number | 12 |
DOIs | |
Publication status | Published - 12 Jun 2013 |
Keywords
- Animals
- Cell Line
- DNA Damage
- DNA-Binding Proteins
- Genomic Instability
- Homologous Recombination
- Humans
- Proteasome Endopeptidase Complex
- Proteolysis
- RecQ Helicases
- Ubiquitin-Protein Ligases
- Ubiquitination