Related Experiment Video

Updated: Jul 17, 2026

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
06:44

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging

Published on: April 28, 2021

LIG1 Loss in TP53-mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP-ATR

Anh Minh Tran Huynh1, Jonathan T Lei2, Rachel Brough3

  • 1Baylor College of Medicine United States.

Molecular Cancer Therapeutics
|July 15, 2026
PubMed

Insights

DNA Ligase I (LIG1) loss in triple-negative breast cancer (TNBC) with TP53 mutations correlates with DNA damage response (DDR) activation. Combining PARP and ATR inhibitors shows promise for treating LIG1-deficient TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Proteogenomic analysis reveals LIG1 loss is linked to chemotherapy resistance in a subset of triple-negative breast cancer (TNBC) with TP53 mutations.
  • TP53 mutations and LIG1 loss are associated with increased DNA damage response (DDR) activity, including homologous recombination, potentially reducing platinum sensitivity.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting DNA repair pathways in LIG1-deficient TNBC.
  • To identify effective drug combinations for LIG1-loss TNBC models.

Main Methods:

  • Utilized unbiased genetic and monotherapy drug screens to identify potential treatments for LIG1-depleted tumors.
  • Conducted a screen of PARP inhibition combined with 120 clinically relevant DDR inhibitors.
  • Evaluated synergistic cytotoxicity of olaparib and ceralasertib in LIG1-loss cell lines and patient-derived xenograft (PDX) models.

Main Results:

  • PARP inhibitors (PARPi) showed modest sensitivity increase in LIG1-depleted TNBC, less than in homologous recombination-deficient models.
  • PARPi sensitivity was significantly enhanced by ATR inhibitors (ATRi) in LIG1-loss cells.
  • The combination of olaparib and ceralasertib demonstrated synergistic cytotoxicity, reduced tumor volume in a LIG1-low PDX model, and enhanced ex vivo cytotoxicity.

Conclusions:

  • LIG1 loss is a potential stratification biomarker for DDR-targeted therapies in TNBC.
  • The combination of ATR inhibitors and PARP inhibitors offers a promising therapeutic strategy for LIG1-deficient TNBC.
  • LIG1 status can guide patient selection for ongoing and future clinical trials involving DDR-targeted combinations in TNBC.

More Related Videos

Visualization of DNA Repair Proteins Interaction by Immunofluorescence07:55

Visualization of DNA Repair Proteins Interaction by Immunofluorescence

Published on: June 26, 2020

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

Related Concept Videos

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...
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...
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...
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...
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...