Dual-utility NLS drives RNF169-dependent DNA damage responses
2017
Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives
cell cycle checkpointactivation but is counterproductive to
high-fidelityDNA repair.
ring fingerprotein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We report here that this attribute is accomplished, in part, by a predicted nuclear localization signal (
NLS) that not only shuttles RNF169 into the nucleus but also promotes its stability by mediating a direct interaction with the ubiquitin-specific protease USP7. Guided by the crystal structure of USP7 in complex with the RNF169
NLS, we uncoupled USP7 binding from its nuclear import function and showed that perturbing the USP7–RNF169 complex destabilized RNF169, compromised
high-fidelityDSB repair, and hypersensitized cells to
poly(
ADP-ribose)
polymeraseinhibition. Finally, expression of USP7 and RNF169 positively correlated in breast cancer specimens. Collectively, our findings uncover an
NLS-mediated bipartite mechanism that supports the nuclear function of a DSB response protein.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
51
References
34
Citations
NaN
KQI