BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

摘要

Abstract Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA , DGCR8 , and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA , DGCR8 , and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells. From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage. Highlights ? BRG1 and SMARCAL1 co-regulate DROSHA, DGCR8, and DICER during DNA damage. ? This co-regulation is required for ncRNA synthesis and 53BP1 foci formation. ? This co-regulation is specific to doxorubicin-induced DNA damage. ? Absence of BRG1 or SMARCAL1 abrogates co-regulation and ncRNA synthesis.