βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1.

Journal Article

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 β2-adrenergic-βarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, βarrestin-1 (βarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether βarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice βarr1 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 βarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of βarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, βarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, βarr1 is an important regulator of double strand break repair, and disruption of the βarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.

Full Text

Duke Authors

Cited Authors

  • Nieto, A; Hara, MR; Quereda, V; Grant, W; Saunders, V; Xiao, K; McDonald, PH; Duckett, DR

Published Date

  • April 2020

Published In

Volume / Issue

  • 27 / 4

Start / End Page

  • 1200 - 1213

PubMed ID

  • 31506606

Pubmed Central ID

  • 31506606

Electronic International Standard Serial Number (EISSN)

  • 1476-5403

Digital Object Identifier (DOI)

  • 10.1038/s41418-019-0406-6

Language

  • eng

Conference Location

  • England