Related Experiment Video

Updated: Mar 16, 2026

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
08:53

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1

Published on: February 17, 2011

15.1K

Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies

Xia Ding1, Arnab Ray Chaudhuri2, Elsa Callen2

  • 1Mouse Cancer Genetics Program, National Cancer Institute, NIH, Frederick, MD 21702, USA.

Nature Communications
|August 9, 2016
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors kill BRCA2-deficient cells. However, inhibiting PARP before BRCA2 loss can lead to synthetic viability, offering a new therapeutic strategy for cancer treatment.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective against BRCA1/2-mutated cancers due to homologous recombination deficiency.
  • The therapeutic effect of PARPi in homologous recombination-proficient cells remains less understood.

Purpose of the Study:

  • To investigate the impact of PARPi on homologous recombination-proficient cells.
  • To explore the mechanism of synthetic lethality and viability in the context of PARP and BRCA2 interactions.

Main Methods:

  • Utilized Brca2(cko/ko) mouse embryonic stem cells (mESCs) with PARP1 knockdown or olaparib pretreatment.
  • Assessed homologous recombination (HR) proficiency and replication fork stability.
  • Evaluated tumorigenesis in Brca2(cko/cko) mice with Parp1 heterozygosity.

Main Results:

  • PARP1 deficiency or inhibition did not restore HR in BRCA2-deficient cells but protected stalled replication forks from degradation.
  • Olaparib pretreatment of HR-proficient cells led to viable Brca2(ko/ko) cells, indicating synthetic viability.
  • Parp1 heterozygosity significantly increased tumorigenesis in the context of BRCA2 loss.

Conclusions:

  • While olaparib is effective against BRCA2-deficient cancers, it can also induce synthetic viability when PARP is inhibited prior to BRCA2 loss.
  • This finding suggests a potential therapeutic window for PARP inhibition in specific cancer contexts, even in HR-proficient cells.

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

9.7K
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

6.0K

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,...
6.5K
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...
10.3K
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...
3.3K
Fixing Double-strand Breaks02:04

Fixing Double-strand Breaks

The double-stranded structure of DNA has two major advantages. First, it serves as a safe repository of genetic information where one strand serves as the back-up in case the other strand is damaged. Second, the double-helical structure can be wrapped around proteins called histones to form nucleosomes, which can then be tightly wound to form chromosomes. This way, DNA chains up to 2 inches long can be contained within microscopic structures in a cell. A double-stranded break not only damages...
15.9K
Mismatch Repair01:20

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
6.9K
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:
8.2K