Related Experiment Video

Updated: Oct 19, 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

Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2

H Lee1, A H Trainer, L S Friedman

  • 1Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.

Molecular Cell
|August 13, 1999
PubMed

Insights

Truncated Brca2 causes DNA damage and cell cycle arrest. Inactivating cell cycle checkpoints with mutant p53 or Bub1 promotes tumor development in Brca2-deficient cells, suggesting a role in inherited breast cancer.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • The murine Brca2 gene is crucial for DNA repair and acts as a tumor suppressor.
  • Truncation of Brca2 paradoxically leads to cell proliferation arrest and chromosomal damage.

Purpose of the Study:

  • To investigate how inactivation of cell cycle checkpoints affects neoplastic transformation in Brca2-deficient cells.
  • To explore the role of mitotic checkpoint genes in the pathogenesis of inherited breast cancer.

Main Methods:

  • Utilizing primary cells homozygous for truncated Brca2.
  • Employing mutant forms of p53 and Bub1 to inactivate cell cycle checkpoints.
  • Analyzing tumors from Brca2-deficient animals for spindle assembly checkpoint function and mutations.

Main Results:

  • Inactivation of cell cycle checkpoints by mutant p53 or Bub1 relieved growth arrest and initiated neoplastic transformation in Brca2-deficient cells.
  • Brca2-deficient tumors showed spindle assembly checkpoint dysfunction and mutations in p53, Bub1, and Mad3L.
  • Mutant forms of Bub1 and p53 suppressed chromosomal aberrations caused by Brca2 truncation.

Conclusions:

  • Inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in inherited breast cancer development.
  • Understanding this cooperation has significant implications for breast cancer treatment strategies.

More Related Videos

In Vitro Evaluation of Oncogenic Transformation in Human Mammary Epithelial Cells09:44

In Vitro Evaluation of Oncogenic Transformation in Human Mammary Epithelial Cells

Published on: September 24, 2020

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

Related Concept Videos

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...
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...
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 daughter...
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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...