Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors

J Vis Exp. 2021 Feb 28:(168). doi: 10.3791/61557.

Abstract

Recent studies have investigated the risks associated with BRCA1 gene mutations using various functional assessment methods such as fluorescent reporter assays, embryonic stem cell viability assays, and therapeutic drug-based sensitivity assays. Although they have clarified a lot of BRCA1 variants, these assays involving the use of exogenously expressed BRCA1 variants are associated with overexpression issues and cannot be applied to post-transcriptional regulation. To resolve these limitations, we previously reported a method for functional analysis of BRCA1 variants via CRISPR-mediated cytosine base editor that induce targeted nucleotide substitution in living cells. Using this method, we identified variants whose functions remain ambiguous, including c.-97C>T, c.154C>T, c.3847C>T, c.5056C>T, and c.4986+5G>A, and confirmed that CRISPR-mediated base editors are useful tools for reclassifying the variants of uncertain significance in BRCA1. Here, we describe a protocol for functional analysis of BRCA1 variants using CRISPR-based cytosine base editor. This protocol provides guidelines for the selection of target sites, functional analysis and evaluation of BRCA1 variants.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • BRCA1 Protein / genetics*
  • Base Sequence
  • Breast Neoplasms / genetics
  • CRISPR-Associated Protein 9 / metabolism
  • Cell Line, Tumor
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics*
  • Female
  • Gene Editing*
  • Genetic Variation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • RNA, Guide, CRISPR-Cas Systems / genetics

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • RNA, Guide, CRISPR-Cas Systems
  • CRISPR-Associated Protein 9