Cancer-associated 53BP1 mutations induce DNA damage repair defects

Cancer Lett. 2021 Mar 31:501:43-54. doi: 10.1016/j.canlet.2020.12.033. Epub 2020 Dec 24.

Abstract

TP53 binding protein 1 (53BP1) plays an important role in DNA damage repair and maintaining genomic stability. However, the mutations of 53BP1 in human cancers have not been systematically examined. Here, we have analyzed 541 somatic mutations of 53BP1 across 34 types of human cancer from databases of The Cancer Genome Atlas, International Cancer Genome Consortium and Catalogue of Somatic Mutations in Cancer. Among these cancer-associated 53BP1 mutations, truncation mutations disrupt the nuclear localization of 53BP1 thus abolish its biological functions in DNA damage repair. Moreover, with biochemical analyses and structural modeling, we have examined the detailed molecular mechanism by which missense mutations in the key domains causes the DNA damage repair defects. Taken together, our results reveal the functional defects of a set of cancer-associated 53BP1 mutations.

Keywords: 53BP1; Cancer-associated mutations; DNA damage repair; Tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Computational Biology
  • DNA Breaks, Double-Stranded*
  • DNA Repair*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Mutation, Missense*
  • Neoplasms / genetics*
  • Tumor Suppressor p53-Binding Protein 1 / chemistry
  • Tumor Suppressor p53-Binding Protein 1 / genetics*

Substances

  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1