Abstract
Ciao1 is a component of the cytosolic iron–sulfur cluster assembly (CIA) complex along with MMS19 and MIP18. Xeroderma pigmentosum group D (XPD), a DNA helicase involved in regulation of cell cycle and transcription, is a CIA target for iron–sulfur (Fe/S) modification. In vivo function of Ciao1 and Xpd in developing animals has been rarely studied. Here, we reveal that Ciao1 interacts with Crumbs (Crb), Galla, and Xpd to regulate organ growth in Drosophila. Abnormal growth of eye by overexpressing Crb intracellular domain (Crbintra) is suppressed by reducing the Ciao1 level. Loss of Ciao1 or Xpd causes similar impairment in organ growth. RNAi knockdown of both Ciao1 and Xpd show similar phenotypes as Ciao1 or Xpd RNAi alone, suggesting their function in a pathway. Growth defects caused by Ciao1 RNAi are suppressed by overexpression of Xpd. Ciao1 physically interacts with Crbintra, Galla, and Xpd, supporting their genetic interactions. Remarkably, Xpd RNAi defects can also be suppressed by Ciao1 overexpression, implying a mutual regulation between the two genes. Ciao1 mutant clones in imaginal discs show decreased levels of Cyclin E (CycE) and death-associated inhibitor of apoptosis 1 (Diap1). Xpd mutant clones share the similar reduction of CycE and Diap1. Consequently, knockdown of Ciao1 and Xpd by RNAi show increased apoptotic cell death. Further, CycE overexpression is sufficient to restore the growth defects from Ciao1 RNAi or Xpd RNAi. Interestingly, Diap1 overexpression in Ciao1 mutant clones induces CycE expression, suggesting that reduced CycE in Ciao1 mutant cells is secondary to loss of Diap1. Taken together, this study reveals new roles of Ciao1 and Xpd in cell survival and growth through regulating Diap1 level during organ development.
Highlights
Iron–sulfur (Fe/S) clusters are essential cofactors that facilitate a number of biological processes including DNA replication and gene regulation[1]
Biogenesis of Fe/S cluster is initiated in the mitochondria, and after being exported to the cytosol, they are processed by the cytosolic iron–sulfur protein assembly (CIA) machinery
This study suggests that Crb function is, in part, mediated through Ciao1-Xpd interaction for cell survival and organ growth
Summary
Iron–sulfur (Fe/S) clusters are essential cofactors that facilitate a number of biological processes including DNA replication and gene regulation[1]. Biogenesis of Fe/S cluster is initiated in the mitochondria, and after being exported to the cytosol, they are processed by the cytosolic iron–sulfur protein assembly (CIA) machinery. The WD40-repeat protein Cia[1] was found as an essential member of the CIA machinery that. Mutational analysis has shown that Cia[1] is essential for viability in yeast and is required for maturation of cytosolic and nuclear Fe/S proteins[5]. XPD has a conserved Fe/S cluster domain near the N-terminus that is essential for its proper helicase activity[9,10]. Fe/S cluster assembly of XPD by the Official journal of the Cell Death Differentiation Association
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