Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

Abstract

Increased expression levels of the RNA splicing regulator Transformer2β (abbreviated Tra2β) have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2β and the highly similar Tra2α protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2β reduces splicing inclusion of a poison exon in the mRNA encoding Tra2α, thereby up-regulating Tra2α protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2β alone. Discovery of this cross-regulation pathway, and its by-pass by joint depletion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 (CHK1) gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.

RNA splicing and splicing regulator changes in prostate cancer pathology

“…As a result of these investigations, future therapies might aim to target specific splice isoforms, for example using antisense oligonucleotide and morpholino techniques that have been developed for other diseases including Duchenne muscular dystrophy and spinal muscular atrophy (Aartsma-Rus and Krieg 2017 ; Rigo et al 2012 ). For example, blocking splicing of exon 3 of CHK1 mRNA might specifically kill cancer cells that rely on CHK1 in the absence of other checkpoints to control replication stress (Best et al 2014 , 2016 ).…”

Celecoxib Conjugated Fluorescent Probe for Identification and Discrimination of Cyclooxygenase-2 Enzyme in Cancer Cells

“…10,11 Cancer cells express elevated level of enzymes or proteins. 9,12,13 COX-2 is an enzyme frequently overexpressed in cancer cells and very less in normal cells. 14−16 Prostaglandin synthesis was regulated by cyclooxygenases (COX-2 or COX-1), which plays a pivotal role in tumor expansion and development.…”

“…Cancer cells express elevated level of enzymes or proteins. ,, COX-2 is an enzyme frequently overexpressed in cancer cells and very less in normal cells. − Prostaglandin synthesis was regulated by cyclooxygenases (COX-2 or COX-1), which plays a pivotal role in tumor expansion and development. , COX-2 is present in various types of tumors including breast, colonic, and cervical cancer cells ,− (such as HT-29, HeLa, MCF-7 cells) and tumor tissues, but COX-2 expresses at low levels in healthy cells (HL-7702 and COS-7 cells), and normal tissues. ,,, Therefore, we selected the COX-2 as a suitable and excellent targetable biomarker to discriminate cancer cells from normal cells.…”