SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation

The SUMO protease SENP6 maintains genomic stability, but mechanistic understanding of this process remains limited. We find that SENP6 deconjugates SUMO2/3 polymers on a group of DNA damage response proteins, including BRCA1-BARD1, 53BP1, BLM and ERCC1-XPF. SENP6 maintains these proteins in a hypo-SUMOylated state under unstressed conditions and counteracts their polySUMOylation after hydroxyurea-induced stress. Co-depletion of RNF4 leads to a further increase in SUMOylation of BRCA1, BARD1 and BLM, suggesting that SENP6 antagonizes targeting of these proteins by RNF4. Functionally, depletion of SENP6 results in uncoordinated recruitment and persistence of SUMO2/3 at UVA laser and ionizing radiation induced DNA damage sites. Additionally, SUMO2/3 and DNA damage response proteins accumulate in nuclear bodies, in a PML-independent manner driven by multivalent SUMO-SIM interactions. These data illustrate coordinated regulation of SUMOylated DNA damage response proteins by SENP6, governing their timely localization at DNA damage sites and nuclear condensation state. The authors show that the SUMO protease SENP6 plays an essential role in maintaining genome integrity by disassembling SUMO2/3 polymers from DNA damage response proteins, thereby preventing their trapping at sites of DNA damage and in nuclear condensates.

Automated summary

The SUMO protease SENP6 plays a crucial role in maintaining genomic stability by disassembling SUMO2/3 polymers from DNA damage response proteins, preventing their trapping at sites of DNA damage and nuclear condensates.