Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

5.9K
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,...
5.9K
DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

9.3K
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...
9.3K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

6.9K
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...
6.9K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

3.9K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Abnormal Proliferation02:23

Abnormal Proliferation

4.6K
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...
4.6K
Long-patch Base Excision Repair01:02

Long-patch Base Excision Repair

7.2K
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:
7.2K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

AE-PocketMiner Uses Attention to Simultaneously Predict Cryptic Pockets and Their Allosteric Coupling.

bioRxiv : the preprint server for biology·2026
Same author

Deep mining of the human antibody repertoire identifies frequent and genetically diverse CDRH3 topologies targetable by vaccination.

Proceedings of the National Academy of Sciences of the United States of America·2026
Same author

How Well Can AI and Physics-Based Simulations Predict the Probability a Cryptic Pocket Is Open?

Journal of chemical theory and computation·2026
Same author

Reduced catalytic activity of KPC β-lactamase can increase ceftazidime resistance.

Communications biology·2026
Same author

Introduction to Markov State Modeling of Conformational Dynamics.

Journal of chemical theory and computation·2026
Same author

How Well Can AI and Physics-Based Simulations Predict the Probability a Cryptic Pocket Is Open?

bioRxiv : the preprint server for biology·2026

Related Experiment Video

Updated: Sep 13, 2025

Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors
09:22

Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors

Published on: February 28, 2021

5.6K

Pathogenic BRCA1 Mutations Disrupt Allosteric Control by BARD1.

Ayan Bhattacharjee1, Gregory R Bowman1

  • 1Departments of Biochemistry & Biophysics and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

The Journal of Physical Chemistry. B
|July 29, 2025
PubMed
Summary

Pathogenic BRCA1 mutations disrupt cancer cell regulation by altering BARD1 binding and protein activity. Understanding these biophysical changes informs the design of new therapeutics for hereditary breast and ovarian cancers.

More Related Videos

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

14.8K
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

9.2K

Related Experiment Videos

Last Updated: Sep 13, 2025

Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors
09:22

Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors

Published on: February 28, 2021

5.6K
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

14.8K
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

9.2K

Area of Science:

  • Biophysics
  • Molecular Biology
  • Computational Biology

Background:

  • Pathogenic mutations in BRCA1 are linked to hereditary breast and ovarian cancers.
  • The precise mechanism by which these mutations disrupt BRCA1 function and lead to oncogenesis remains unclear.
  • BRCA1's E3 ligase activity is regulated by binding to BARD1.

Purpose of the Study:

  • To investigate the allosteric mechanisms by which BARD1 binding activates BRCA1 E3 ligase activity.
  • To elucidate how pathogenic mutations in BRCA1 perturb these activation mechanisms.
  • To provide mechanistic insights for designing therapeutics targeting BRCA1.

Main Methods:

  • Atomistic molecular dynamics simulations.
  • Markov state modeling.
  • Analysis of allosteric coupling between the BARD1 binding site and the E2 interface.

Main Results:

  • BARD1 binding selects for and stabilizes active conformational states of BRCA1.
  • The BARD1 binding site (helix bundle) is allosterically coupled to the E2 interface.
  • Pathogenic mutations destabilize these active states, while hyperactive mutations increase their likelihood.

Conclusions:

  • BARD1-mediated activation of BRCA1 is a conformational selection process.
  • Pathogenic BRCA1 mutations exert their effect by allosterically disrupting these active conformations.
  • These findings offer a mechanistic basis for developing small molecule therapeutics to restore BRCA1 function.