Abstract
SMARCAL1, a member of the SWI2/SNF2 protein family, stabilizes replication forks during DNA damage. In this manuscript, we provide the first evidence that SMARCAL1 is also a transcriptional co-regulator modulating the expression of c-Myc, a transcription factor that regulates 10–15% genes in the human genome. BRG1, SMARCAL1 and RNAPII were found localized onto the c-myc promoter. When HeLa cells were serum starved, the occupancy of SMARCAL1 on the c-myc promoter increased while that of BRG1 and RNAPII decreased correlating with repression of c-myc transcription. Using Active DNA-dependent ATPase A Domain (ADAAD), the bovine homolog of SMARCAL1, we show that the protein can hydrolyze ATP using a specific region upstream of the CT element of the c-myc promoter as a DNA effector. The energy, thereby, released is harnessed to alter the conformation of the promoter DNA. We propose that SMARCAL1 negatively regulates c-myc transcription by altering the conformation of its promoter region during differentiation.
Highlights
The transcription factor c-myc, a leucine zipper protein, regulates the expression of 10–15% of human genes, playing an important role in cell proliferation, differentiation, growth and survival; overexpression of the protein is associated with cancer[18,19,20,21]
We found that SMARCAL1 regulates differentiation of K562 cells in response to phorbol myristate acetate (PMA) by transcriptionally repressing c-myc expre transcriptionally repressing c-myc expression leading us to leading us to propose that the phenotypic manifestation of SIOD could be due to the changes in gene expression profiles of key transcription factors which are directly or indirectly regulated by SMARCAL1 with the negative regulation of c-myc presented in this paper being one such example
Baradaran-Heravi et al have hypothesized that SMARCAL1 can possibly regulate genes like c-kit and c-myc by altering the promoter structure4. c-kit expression is regulated by G-quadruplex formation, a feature that is shared by another transcription factor, c-myc, which regulates 10–15% of genes in mammalian cells
Summary
The transcription factor c-myc, a leucine zipper protein, regulates the expression of 10–15% of human genes, playing an important role in cell proliferation, differentiation, growth and survival; overexpression of the protein is associated with cancer[18,19,20,21]. A GC-rich region, known as CT element, present −142 to −115 bp upstream of the P1 promoter, is the major regulator of c-myc expression by the formation of G-quadruplex and I-motif[24,25,26]. We have explored the role of BRG1 and SMARCAL1 in regulating the expression of c-myc. We have shown that both BRG1 and SMARCAL1 bind to a 159 bp DNA segment upstream of the CT element which will be referred to as Myc_B159 in the remaining manuscript. We found that SMARCAL1 regulates differentiation of K562 cells in response to phorbol myristate acetate (PMA) by transcriptionally repressing c-myc expre transcriptionally repressing c-myc expression leading us to leading us to propose that the phenotypic manifestation of SIOD could be due to the changes in gene expression profiles of key transcription factors which are directly or indirectly regulated by SMARCAL1 with the negative regulation of c-myc presented in this paper being one such example
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