| First Author | Nieto A | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 4 | Pages | 1200-1213 |
| PubMed ID | 31506606 | Mgi Jnum | J:295978 |
| Mgi Id | MGI:6455106 | Doi | 10.1038/s41418-019-0406-6 |
| Citation | Nieto A, et al. (2020) betaarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1. Cell Death Differ 27(4):1200-1213 |
| abstractText | Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the beta2-adrenergic-betaarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, betaarrestin-1 (betaarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether betaarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice betaarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that betaarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of betaarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, betaarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, betaarr1 is an important regulator of double strand break repair, and disruption of the betaarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation. |
