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Related Concept Videos

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...
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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...
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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...
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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.
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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...

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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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BCL2 suppresses PARP1 function and nonapoptotic cell death.

Chaitali Dutta1, Tovah Day, Nadja Kopp

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

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Researchers discovered that the BCL2 protein directly interacts with and inhibits the DNA repair enzyme PARP1. Disrupting this BCL2-PARP1 interaction may offer a new therapy for apoptosis-resistant cancers.

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Published on: April 28, 2021

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • BCL2 is a key antiapoptotic protein, crucial for survival in many cancers like lymphomas.
  • Tumor cells often develop resistance to apoptosis-inducing therapies by upregulating BCL2.
  • PARP1 is an enzyme involved in DNA repair, essential for cancer cell survival.

Purpose of the Study:

  • To investigate the interaction between BCL2 and PARP1.
  • To determine the functional consequences of this interaction on PARP1 activity and DNA repair.
  • To explore the therapeutic potential of targeting the BCL2-PARP1 interaction.

Main Methods:

  • Identified direct interaction between BCL2 and PARP1 using biochemical assays.
  • Utilized BH3 mimetic ABT-737 to disrupt the BCL2-PARP1 complex.
  • Assessed PARP1 enzymatic activity and DNA repair capacity in cancer cells.
  • Evaluated cell death and survival in response to BCL2 expression and PARP inhibitors.

Main Results:

  • BCL2 directly binds to PARP1, suppressing its enzymatic activity and DNA repair function.
  • BH3 mimetic ABT-737 dissociates PARP1 from BCL2, restoring PARP1 activity and promoting nonapoptotic cell death.
  • BCL2 expression significantly reduced the survival of PARP inhibitor-sensitive cancer cells, an effect reversed by ABT-737.
  • This novel cell death mechanism was effective even in cells resistant to single-agent ABT-737.

Conclusions:

  • A novel interaction between BCL2 and PARP1 inhibits PARP1's enzymatic activity and DNA repair.
  • Targeting the BCL2-PARP1 interaction represents a potential therapeutic strategy for BCL2-expressing, apoptosis-resistant tumors.
  • This finding opens new avenues for cancer treatment by exploiting the interplay between apoptosis regulation and DNA repair pathways.