來自德克薩斯大學(xué)M.D. Anderson癌癥中心的研究人員發(fā)現(xiàn)了一個(gè)單獨(dú)的基因,，可以作為以前沒有確定下來的腫瘤的抑制子,。這個(gè)基因可以執(zhí)行一個(gè)關(guān)鍵的作用，引發(fā)人類基因組的兩種DNA損傷檢測和修復(fù)途徑,。這一研究成果公布在Cancer Cell雜志上,。
研究人員說一種被稱為BRIT1的基因被發(fā)現(xiàn)在人類的卵巢，乳房和前列腺癌癥細(xì)胞系低表達(dá),。作者表示缺失了BRIT1基因看上去是對癌癥的起始和進(jìn)程是一個(gè)關(guān)鍵的改變,，更深的理解這個(gè)基因的功能可以對未來的治療癌癥的方法有一個(gè)顯著的貢獻(xiàn)。
這項(xiàng)研究的作者,，分子治療學(xué)的助理教授Shiaw-Yih Lin說到,，“破壞了BRIT1基因的功能就可以消除DNA損傷反應(yīng)以及隨之帶來的基因組的不穩(wěn)定性。”而基因組的不穩(wěn)定性的后果就是帶來癌癥細(xì)胞的起始,，增殖和擴(kuò)散,。
英文原文：
Researchers identify gene as DNA guardian and sworn enemy of tumours
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.
