Related Experiment Video

Updated: Oct 29, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
09:24

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

Published on: August 12, 2015

9.3K

Suppression of DNA Polymerase β Activity Is Synthetically Lethal in BRCA1-Deficient Cells

Shelby C Yuhas1, Alok Mishra2,3, Theodore L DeWeese2,3

  • 1Department of Chemistry, Johns Hopkins University, 3400 N. Charles Street, Baltimore, Maryland 21218, United States.

ACS Chemical Biology
|July 9, 2021
PubMed

Insights

Targeting DNA polymerase β (Pol β) offers a new synthetic lethal strategy for BRCA1-deficient cancers. Inhibiting Pol β shows significant cytotoxicity in BRCA1-deficient ovarian and breast cancer cells, similar to existing treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in the BRCA1 tumor suppressor gene increase cancer risk.
  • BRCA1-deficient cells exhibit defects in DNA double-strand break repair.
  • Current treatments exploit synthetic lethality, such as inhibiting poly(ADP-ribose) polymerase 1 (PARP1) in BRCA1-deficient cancers.

Purpose of the Study:

  • To identify and validate alternative synthetic lethal targets in BRCA1-deficient cancer cells.
  • To investigate the potential of DNA polymerase β (Pol β) as a synthetic lethal target.

Main Methods:

  • Utilizing siRNA to knockdown Pol β expression in cancer cells.
  • Treating cancer cells with a specific Pol β pro-inhibitor (pro-1).
  • Comparing the cytotoxic effects in BRCA1-deficient cells versus BRCA1-complemented cells.

Main Results:

  • siRNA-mediated knockdown of Pol β induced cytotoxicity in BRCA1-deficient ovarian cancer cells.
  • Treatment with pro-1 demonstrated significant toxicity in BRCA1-deficient ovarian and breast cancer cells.
  • BRCA1-complemented cells showed markedly reduced susceptibility to both Pol β inhibition strategies.
  • The toxicity of pro-1 in BRCA1-deficient cells was comparable to that of the established drug Olaparib.

Conclusions:

  • DNA polymerase β (Pol β) exhibits a synthetically lethal interaction with BRCA1 deficiency.
  • Pol β represents a novel and potentially effective synthetic lethal target for cancer therapy.
  • Targeting Pol β offers a promising alternative therapeutic strategy for BRCA1-deficient cancers.

More Related Videos

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA108:53

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

Published on: February 17, 2011

14.9K
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

5.7K

Related Concept Videos

Translesion DNA Polymerases02:10

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
10.3K
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,...
6.0K
Proofreading01:31

Proofreading

Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template DNA strand. DNA polymerase has a higher affinity to add the correct base and ensures fidelity during DNA replication. Furthermore,  it exhibits proofreading activity during replication, using an exonuclease domain that cuts off incorrect nucleotides from the nascent DNA strand.
Errors During Replication are Corrected by the DNA Polymerase...
7.3K
Proofreading01:43

Proofreading

Overview
57.5K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.8K
DNA Damage can Stall the Cell Cycle02:37

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...
9.6K