Protein DAP-3 that Drives Cancer Progress

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Scientists from the Cancer Science Institute of Singapore have discovered a protein that drives the growth of cancers.

Cancer is caused by certain changes to genes that control the way cells growth and division functions. Certain gene changes can cause cells to evade normal growth controls.

Scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have discovered a protein that drives the growth of cancers of the esophagus or liver as result of their researchs.

This protein is the death associated protein 3 (DAP3), which represses adenosine-to-inosine (A-to-I) RNA editing.

Mechanism of Protein DAP3

RNAs convert the genetic information stored in DNA to proteins, also play crucial regulatory roles in various biological processes.

Transcriptional modifications contribute to transcriptome diversity. However, what makes transcriptional modifications important is that Transcriptional modifications can do this without having to make hard-wired mutations at the DNA level. A-to-I RNA editing is one of the post-transcriptional modification that affects the information encoded from DNA to RNA to protein.

A-to-I editing in double-stranded RNA (dsRNA), catalyzed by adenosine deaminase acting on RNA (ADAR) family of enzymes(ADAR1 and ADAR2), is the most common type of RNA editing in mammals.

Protein DAP3 in Cancer

By inhibiting A-to-I RNA editing, DAP3 acts as an oncogene. Oncogene is a gene that has the potential to cause cancer. Results of this study offers the potential of developing novel drugs that target DAP3 for cancer treatment. DAP3 mainly functions as a potent repressor of A-to-I RNA editing in cancer cells.

Binding of ADARs to editing substrates and ADAR homodimerization are two critical factors required for A-to-I RNA editing. DAP3 disturbs ADAR1 homodimerization and inhibits the binding of ADAR2 protein to its dsRNA substrates. DAP3 represses A-to-I RNA editing without affecting ADAR expression.

To understand the clinical relevance of DAP3 in cancer, the CSI Singapore research team analyzed DAP3 expression using the RNA-seq data from the Cancer Genome Atlas (TCGA) database.

The Cancer Genome Atlas, a landmark cancer genomics program, molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types.  Scientists observed that DAP3 was significantly up-regulated in tumor samples as compared to their corresponding nontumor tissues across 17 of 22 cancer types.

The study was led by Assistant Professor Polly Chen, and was published in the scientific journal Science Advances on 17 June 2020.

Reference: Yablonovitch AL, Deng P, Jacobson D, Li JB (2017) The evolution and adaptation of A-to-I RNA editing. PLOS Genetics 13(11): e1007064.

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