Researchers identify gene as DNA guardian and sworn enemy of tumours

By Wai Lang Chu

- Last updated on GMT

Related tags: Cancer, Gene

Researchers have identified a gene that plays a pivotal role in
initiating two DNA damage detection and repair pathways in the
human genome, suggesting that it functions as a tumour suppressor.

This latest discovery represents another potential target for cancer, which further understanding of its function may contribute to novel, therapeutic approaches to cancer.

Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis,' which implies that both alleles that code for a particular gene must be affected before an effect is manifested.

This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53.

The gene, BRIT1 is under-expressed in human ovarian, breast and prostate cancer cell lines and previous research has already identified defects in BRIT1 seem to be a key pathological alteration in cancer initiation and progression

"Disruption of BRIT1 function abolishes DNA damage responses and leads to genomic instability,"​ said senior author Shiaw-Yih Lin, assistant professor in the Department of Molecular Therapeutics at M. D. Anderson.

In a series of laboratory experiments, Lin and colleagues show that BRIT1 activates two of these checkpoint pathways.

The ATM pathway springs into action in response to damage caused by ionising radiation. The ATR pathway responds to DNA damage caused by ultraviolet radiation.

By using small interfering RNA (siRNA) to silence the BRIT1 gene, the scientists shut down both checkpoint pathways in cells exposed to either type of radiation.

Researchers then used siRNA to silence the gene in normal human mammary epithelial cells (HMEC).

The results demonstrated that inactivation of the gene caused chromosomal aberrations in 21.2 to 25.6 per cent of cells.

Control group HMEC had no cells with chromosomal aberrations. In cells with the gene silenced that were then exposed to ionising radiation, 80 per cent of cells had chromosomal aberrations.

"We also found that BRIT1 expression is aberrant in several forms of human cancer,"​ Lin said.

The team found reduced expression of the gene in 35 of 87 cases of advanced epithelial ovarian cancer. They also found reduced expression in breast and prostate cancer tissue compared with non-cancerous cells.

A signalling network of molecular checkpoint pathways protects the human genome by detecting DNA damage, initiating repair and halting division of the damaged cell so that it does not replicate.

Genetic analysis of breast cancer specimens revealed a truncated, dysfunctional version of the BRIT1 protein in one sample.

Loss of the DNA damage checkpoint function and the ability to proliferate indefinitely are two cellular changes required for the development of cancer. Lin and colleagues have now tied the gene to both factors.

They previously identified BRIT1 as a repressor of hTERT, a protein that when reactivated immortalizes cells, allowing them to multiply indefinitely.

The researchers report their findings in the in >Cancer Cell.

Related topics: Preclinical Research

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