title: Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation.
abstract: 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.
authors.affiliation: a Laboratory of Cytometry; Nencki Institute of Experimental Biology ; Warsaw , Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Podszywalow-Bartnicka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Wolczyk
authors.forename: Monika
authors.initials: M
authors.lastname: Kusio-Kobialka
authors.forename: Kamila
authors.initials: K
authors.lastname: Wolanin
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Skowronek
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Yashodhara
authors.initials: Y
authors.lastname: Dasgupta
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwocka
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C581634:BCR-ABL1 fusion protein, human; D019313:BRCA1 Protein; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C489665:Tial1 protein, mouse; D016044:Fusion Proteins, bcr-abl
keywords: ARE, AU-rich element; ATM, Ataxia telangiectasia mutated kinase; ATR, Ataxia telangiectasia and Rad3-related kinase; BCR-ABL; BRCA1; BRCA1, Breast cancer type 1 susceptibility; CML, chronic myeloid leukemia; DNA damage response; HuR; HuR, Hu antigen R (alternative name: ELAV-like protein 1); TIAR; TIAR, TIA1 cytotoxic granule-associated RNA-binding protein-like 1; UPR, unfolded protein response; UTR, untranslated region; cell cycle; eIF, eukaryotic initiation factor; mRNA binding protein; stress response; synthetic lethality; translation