MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.
The function of many DNA metabolism proteins depends on their ability to coordinate an iron-sulfur (Fe-S) cluster. Biogenesis of Fe-S proteins is a multistep process that takes place in mitochondria and the cytoplasm, but how it is linked to nuclear Fe-S proteins is not known. Here, we demonstrate that MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18. Cytoplasmic MMS19 also binds to multiple nuclear Fe-S proteins involved in DNA metabolism. In the absence of MMS19, a failure to transfer Fe-S clusters to target proteins is associated with Fe-S protein instability and preimplantation death of mice in which Mms19 has been knocked out. We propose that MMS19 functions as a platform to facilitate Fe-S cluster transfer to proteins critical for DNA replication and repair.
DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
Kerstin
K
Gari
Ana María
AM
León Ortiz
Valérie
V
Borel
Helen
H
Flynn
J Mark
JM
Skehel
Simon J
SJ
Boulton
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D006864:Hydrogenase / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D056511:Metallochaperones / Q000378:metabolism; D008667:Metalloproteins; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D055550:Protein Stability; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051759:Xeroderma Pigmentosum Group D Protein / Q000378:metabolism
C112111:CIAO1 protein, human; C569498:CIAO2B protein, human; C516542:CIAO3 protein, human; D002352:Carrier Proteins; D007506:Iron-Sulfur Proteins; C416322:MMS19 protein, human; C467337:MMS19 protein, mouse; D056511:Metallochaperones; D008667:Metalloproteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D004247:DNA; D006864:Hydrogenase; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human