Related Experiment Video

Updated: Jan 2, 2026

gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair
08:15

gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair

Published on: October 6, 2014

12.6K

BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance

Yifan Wang1, Andrea J Bernhardy1, Joseph Nacson1,2

  • 1Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Nature Communications
|December 13, 2019
PubMed

Insights

BRCA1 gene rearrangements in intron 15 can lead to resistance against PARP inhibitor (PARPi) therapy by producing functional BRCA1 protein variants. These variants promote DNA repair, enabling cancer cell proliferation despite PARPi treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRCA1 mutations confer sensitivity to PARP inhibitors (PARPi) due to impaired DNA repair.
  • Resistance to PARPi therapy is a significant clinical challenge in BRCA1-mutated cancers.
  • Correct folding and stability of BRCA1 protein, particularly the BRCT domain, are crucial for its function.

Purpose of the Study:

  • To investigate the mechanisms underlying PARPi resistance in BRCA1 mutant cancers.
  • To identify genetic alterations in BRCA1 that confer resistance to PARPi therapy.
  • To explore the role of BRCA1 protein isoforms in homology-dependent DNA repair and PARPi resistance.

Main Methods:

  • Analysis of cell lines and patient-derived tumors with BRCA1 BRCT domain mutations.
  • Detection of BRCA1 protein expression in resistant cancer models.
  • Peptide analysis to identify specific protein residues in chemo-resistant cancers.
  • Investigation of BRCA1 gene rearrangements, including Alu element involvement, in intron 15.

Main Results:

  • Highly disruptive BRCA1 BRCT domain mutations did not always lead to protein degradation, with detectable BRCA1 protein expression in resistant cases.
  • Chemo-resistant cancers harbored BRCA1 gene breakpoints within Alu elements in intron 15, causing partial gene duplications, inversions, or translocations.
  • These rearrangements generated BRCA1 isoforms lacking the mutated BRCT domain, which escaped proteasomal degradation.
  • BRCA1 BRCT domain-deficient isoforms supported homology-dependent DNA repair, contributing to PARPi resistance.

Conclusions:

  • Alu-mediated BRCA1 gene rearrangements in intron 15 generate hypomorphic BRCA1 proteins that confer PARPi resistance.
  • These specific BRCA1 gene rearrangements may serve as a predictive biomarker for PARPi resistance.
  • Understanding these resistance mechanisms is crucial for optimizing cancer treatment strategies.

More Related Videos

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells09:24

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

9.5K
Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors09:22

Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors

Published on: February 28, 2021

5.9K

Related Concept Videos

Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.2K
Base Excision Repair01:54

Base Excision Repair

One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
The first step of...
25.8K
Long-patch Base Excision Repair01:02

Long-patch Base Excision Repair

Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.8K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.9K
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.0K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.6K