The 53BP1–USP28 complex enhances p53-dependent transcription to promote tumor suppression.

  • Major finding: The 53BP1–USP28 complex enhances p53-dependent transcription to promote tumor suppression.

  • Mechanism: 53BP1 binds to p53 and USP28 via two distinct BRCT domain surfaces to promote p53–DNA interactions.

  • Impact: 53BP1 mediates tumor suppression through separate p53 regulation and DNA repair functions.

The role of the tumor suppressor protein 53BP1, initially identified as a p53-interacting protein, in nonhomologous end-joining (NHEJ) DNA double-strand break (DSB) repair has been well characterized, but the function of the 53BP1–p53 interaction remains unclear. To determine the role of 53BP1 in p53-mediated signaling, Cuella-Martin and colleagues generated 53BP1-null cells and tested their sensitivity to Nutlin-3, a small-molecule antagonist of the p53 inhibitor MDM2 that results in p53 stabilization and activation. 53BP1-null cells exhibited reduced growth arrest and disrupted expression of p53 targets including p21 and MDM2 in response to Nutlin-3 treatment, suggesting that 53BP1 loss disrupted p53 function. RNA sequencing of 53BP1-null cells after Nutlin-3 treatment or ionizing radiation indicated that transactivation of p53-dependent genes was diminished, further indicating that 53BP1 is required for p53-dependent transcription. The 53BP1 tandem BRCT domain interaction with p53 was required for normal p53 function, but the BRCT domain was not required for the canonical NHEJ functions of 53BP1, indicating that the DSB-repair and p53-regulating functions of 53BP1 are distinct. The BRCT domain of 53BP1 bound to the ubiquitin-specific protease USP28 on a surface distinct from p53, allowing 53BP1 to simultaneously bind to both USP28 and p53, and suggesting a potential role for USP28 and 53BP1 in regulating p53. Consistent with a cooperative role for USP28 and 53BP1 in p53 regulation, USP28-null cells exhibited similar resistance to Nutlin-3 as 53BP1-null cells and deficient MDM2 and p21 induction, effects that were not magnified by double deletion. Mechanistically, 53BP1 and USP28 enhanced p53-dependent transcriptional programs by promoting p53 binding to p53-response elements at target gene promoters. Collectively, these findings indicate that 53BP1 enhances p53 transcription independent of its function in DNA DSB repair.

Cuella-Martin R, Oliveira C, Lockstone HE, Snellenberg S, Grolmusova N, Chapman JR. 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms. Mol Cell 2016 Aug 18 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.