Related Experiment Video

Updated: Jul 11, 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

9.1K

PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint

Jian Wang1, Yuke Chen2, Shiwei Li1

  • 1Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China.

The Journal of Clinical Investigation
|November 7, 2023
PubMed

Insights

Inactivating BRCA2 mutations increase prostate cancer risk. Researchers found that inhibiting NSFL1C promotes survival in BRCA2-deficient cells by suppressing the spindle assembly checkpoint (SAC).

Area of Science:

  • Oncology
  • Genetics
  • Cell Biology

Background:

  • Mutations in the BRCA2 tumor suppressor gene are linked to increased prostate cancer risk.
  • BRCA2 inactivation compromises genetic stability, yet cancer cells adapt for malignant proliferation.
  • Understanding these adaptive mechanisms is key to developing therapies for BRCA2-mutated tumors.

Purpose of the Study:

  • To identify mechanisms of adaptation and survival in BRCA2-deficient cancer cells.
  • To explore potential therapeutic strategies targeting these adaptive pathways.

Main Methods:

  • Forward genetic synthetic viability screening in Caenorhabditis elegans brc-2 mutants.
  • Investigated the role of NSFL1C (mammalian ortholog of CeUBXN-2) in BRCA2-deficient cells.
  • Analyzed the molecular mechanism involving NSFL1C, USP9X, AURKB, VCP, and the spindle assembly checkpoint (SAC).

Main Results:

  • Inactivation of Ceubxn-2 rescued viability in Cebrc-2 mutants.
  • Loss of NSFL1C suppressed SAC activation and promoted survival in BRCA2-deficient cells.
  • NSFL1C recruits USP9X to inhibit AURKB polyubiquitination and its removal from centromeres, preventing SAC activation.
  • SAC inactivation is prevalent in BRCA2-deficient prostate cancer patients.

Conclusions:

  • NSFL1C plays a critical role in the survival adaptation of BRCA2-deficient cells.
  • Targeting PP2A inhibitors could reactivate SAC and induce synthetic lethality in BRCA2-deficient prostate tumors.
  • This study offers novel therapeutic targets beyond DNA damage repair pathways for BRCA2-deficient cancers.
Keywords:
Cell BiologyDNA repairOncologyProstate cancerTumor suppressors

More Related Videos

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells15:53

Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells

Published on: August 21, 2013

15.0K
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel06:44

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel

Published on: September 8, 2017

13.4K

Related Concept Videos

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...
4.5K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.4K
The Spindle Assembly Checkpoint02:19

The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
3.2K
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...
9.2K
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,...
5.8K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
6.6K