APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer

Manikandan Periyasamy1, Hetal Patel1, Chun-Fui Lai1

  • 1Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.

Cell Reports
|September 29, 2015
PubMed

Insights

APOBEC3B (A3B) deaminates DNA at estrogen receptor binding sites, promoting gene expression in ER+ breast cancer. This mechanism, involving DNA repair pathways, is linked to poorer patient survival.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Estrogen receptor alpha (ERα) is a critical driver in many breast cancers.
  • The precise mechanisms by which ERα regulates gene expression are complex and still under investigation.

Purpose of the Study:

  • To investigate the role of APOBEC3B (A3B) in the regulation of gene expression by ERα.
  • To elucidate the molecular mechanisms by which A3B influences ERα target gene activity.

Main Methods:

  • Assessing C-to-U deamination at ER binding regions.
  • Investigating DNA strand break generation via base excision repair (BER).
  • Analyzing repair by non-homologous end-joining (NHEJ) pathways.

Main Results:

  • APOBEC3B (A3B) causes C-to-U deamination at ER binding regions, facilitating ER-mediated gene regulation.
  • A3B-induced deamination triggers DNA strand breaks, repaired by BER and NHEJ.
  • Transient deamination by A3B promotes chromatin modification and remodelling at ER target gene regulatory regions, enhancing their expression.

Conclusions:

  • APOBEC3B is essential for ER-mediated gene regulation in ER+ breast cancer.
  • The A3B-driven mechanism involving DNA deamination and repair influences chromatin dynamics and gene expression.
  • A3B expression correlates with poor patient survival in ER+ breast cancer, highlighting its clinical relevance.

Related Concept Videos

RNA Editing02:23

RNA Editing

RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the...
10.2K
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
69
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
8.4K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K
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...
6.2K
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...
5.4K