BRCA1 tumor suppressor regulates crucial cellular processes involved in DNA 
damage repair and cell cycle control. We showed that expression of BCR-ABL1 
correlates with decreased level of BRCA1 protein, which promoted aberrant 
mitoses and aneuploidy as well as altered DNA damage response. Using polysome 
profiling and luciferase-BRCA1 3'UTR reporter system here we demonstrate that 
downregulation of BRCA1 protein in CML is caused by inhibition of BRCA1 mRNA 
translation, but not by increased protein degradation or reduction of mRNA level 
and half-life. We investigated 2 mRNA-binding proteins - HuR and TIAR showing 
specificity to AU-Rich Element (ARE) sites in 3'UTR of mRNA. BCR-ABL1 promoted 
cytosolic localization of TIAR and HuR, their binding to BRCA1 mRNA and 
formation of the TIAR-HuR complex. HuR protein positively regulated BRCA1 mRNA 
stability and translation, conversely TIAR negatively regulated BRCA1 
translation and was found localized predominantly in the cytosolic stress 
granules in CML cells. TIAR-dependent downregulation of BRCA1 protein level was 
a result of ER stress, which is activated in BCR-ABL1 expressing cells, as we 
previously shown. Silencing of TIAR in CML cells strongly elevated BRCA1 level. 
Altogether, we determined that TIAR-mediated repression of BRCA1 mRNA 
translation is responsible for downregulation of BRCA1 protein level in BCR-ABL1 
-positive leukemia cells. This mechanism may contribute to genomic instability 
and provide justification for targeting PARP1 and/or RAD52 to induce synthetic 
lethality in "BRCAness" CML and BCR-ABL1 -positive ALL cells.