Abstract
ABSTRACTMms19 encodes a cytosolic iron-sulphur assembly component. We found that Drosophila Mms19 is also essential for mitotic divisions and for the proliferation of diploid cells. Reduced Mms19 activity causes severe mitotic defects in spindle dynamics and chromosome segregation, and loss of zygotic Mms19 prevents the formation of imaginal discs. The lack of mitotic tissue in Mms19P/P larvae can be rescued by overexpression of the Cdk-activating kinase (CAK) complex, an activator of mitotic Cdk1, suggesting that Mms19 functions in mitosis to allow CAK (Cdk7/Cyclin H/Mat1) to become fully active as a Cdk1-activating kinase. When bound to Xpd and TFIIH, the CAK subunit Cdk7 phosphorylates transcriptional targets and not cell cycle Cdks. In contrast, free CAK phosphorylates and activates Cdk1. Physical and genetic interaction studies between Mms19 and Xpd suggest that their interaction prevents Xpd from binding to the CAK complex. Xpd bound to Mms19 therefore frees CAK complexes, allowing them to phosphorylate Cdk1 and facilitating progression to metaphase. The structural basis for the competitive interaction with Xpd seems to be the binding of Mms19, core TFIIH and CAK to neighbouring or overlapping regions of Xpd.
Highlights
Considering the countless insults that DNA and chromosomes have to sustain, it is amazing how faithfully the genome is duplicated and passed on to daughter cells during mitosis. mms19 was first identified in Saccharomyces cerevisiae as a gene that is necessary for repairing alkylated DNA and for the removal of ultraviolet lightinduced pyrimidine dimers by the nucleotide excision repair (NER) pathway (Prakash and Prakash, 1977, 1979)
Human and yeast MMS19 are part of the late-acting cytoplasmic iron-sulphur assembly (CIA) machinery that facilitates the transfer of Fe-S clusters to their target proteins (Gari et al, 2012; Stehling et al, 2012)
Human MMS19 performs this activity as part of a cytoplasmic complex with the other components of the CIA machinery, CIAO1, MIP18 and IPO1
Summary
Considering the countless insults that DNA and chromosomes have to sustain, it is amazing how faithfully the genome is duplicated and passed on to daughter cells during mitosis. mms was first identified in Saccharomyces cerevisiae as a gene that is necessary for repairing alkylated DNA and for the removal of ultraviolet lightinduced pyrimidine dimers by the nucleotide excision repair (NER) pathway (Prakash and Prakash, 1977, 1979). Reduction of MMS19 activity in higher eukaryotes causes additional phenotypes such as defective mitotic spindles and chromosome segregation defects, extended telomeres and defects in methionine synthesis It appears that MMS19 might have diverse functions in eukaryotes
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