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A human protein related to yeast Cdc6p.

ABSTRACT: The unstable proteins Cdc6p and cdc18+ are essential and rate limiting for the initiation of DNA replication in Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively, and also participate in checkpoint controls that ensure DNA replication is completed before mitosis is initiated. We have identified Xenopus and human proteins closely related to Cdc6p/cdc18. The human protein, p62(cdc6), is encoded on chromosome 17q21.3 and includes putative cyclin-dependent kinase phosphorylation sites, destruction boxes, a nucleotide binding/ATPase domain, and a potential leucine zipper. Expression of p62(cdc6) mRNA and protein is suppressed in human diploid fibroblasts made quiescent by serum starvation, and peaks as cells reenter the cell cycle and replicate DNA following serum stimulation. Conservation of structure among proteins involved in initiation suggests that fundamental features of replication complexes are maintained in all eukaryotes.

SUBMITTER: Williams RS

PROVIDER: S-EPMC19260 | biostudies-literature | 1997 Jan

REPOSITORIES: biostudies-literature

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A human protein related to yeast Cdc6p.

Williams R S RS Shohet R V RV Stillman B B

Proceedings of the National Academy of Sciences of the United States of America 19970101 1

The unstable proteins Cdc6p and cdc18+ are essential and rate limiting for the initiation of DNA replication in Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively, and also participate in checkpoint controls that ensure DNA replication is completed before mitosis is initiated. We have identified Xenopus and human proteins closely related to Cdc6p/cdc18. The human protein, p62(cdc6), is encoded on chromosome 17q21.3 and includes putative cyclin-dependent kinase phosphorylation s ...[more]

PMID: 8990175

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Project description:Simple Summary DnaJB6 is a human cellular protein quality control factor that prevents diverse peptides from forming disease-associated amyloid, a highly ordered fibrous protein aggregate. DnaJB6 protects human cells, animals and yeast from toxicity caused by amyloids composed of Huntington’s-related polyglutamine, Parkinson’s-related α-synuclein, and ALS- associated TDP-43, and it cures yeast of endogenous prions (infectious amyloids). However, structurally different amyloids of one and the same prion protein, and prions composed of them, can be insensitive to anti-amyloid activity of DnaJB6. This limitation raises concerns about developing DnaJB6 as a therapeutic for amyloid diseases. Prions showing this insensitivity are highly toxic to yeast with reduced function of Sis1, a yeast protein related to DnaJB6. To begin assessing how DnaJB6 might act on amyloid in cells we tested if DnaJB6 could protect yeast from this toxicity. Although it does not eliminate the prion, it protects cells from prion toxicity, but differently than Sis1. Our work provides insight into how human DnaJB6 counteracts cellular toxicity caused by amyloid and establishes an in vivo genetic system useful for studying DnaJB6-amyloid interactions to decipher its mechanisms of action. Abstract Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington’s, Alzheimer’s, and Parkinson’s diseases, respectively. In yeast, amyloid-based [PSI+] prions, which rely on the related JDP Sis1 for replication, have a latent toxicity that is exposed by reducing Sis1 function. Anti-amyloid activity of DnaJB6 is very effective against weak [PSI+] prions and the Sup35 amyloid that composes them, but ineffective against strong [PSI+] prions composed of structurally different amyloid of the same Sup35. This difference reveals limitations of DnaJB6 that have implications regarding its therapeutic use for amyloid disease. Here, we find that when Sis1 function is reduced, DnaJB6 represses toxicity of strong [PSI+] prions and inhibits their propagation. Both Sis1 and DnaJB6, which are regulators of protein chaperone Hsp70, counteract the toxicity by reducing excessive incorporation of the essential Sup35 into prion aggregates. However, while Sis1 apparently requires interaction with Hsp70 to detoxify [PSI+], DnaJB6 counteracts prion toxicity by a different, Hsp70-independent mechanism.

Dataset Information

A human protein related to yeast Cdc6p.

Publications

A human protein related to yeast Cdc6p.

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