Burke DJ et al. (1982) Worm Breeder's Gazette

Burke DJ, Ward S

[Worm Breeder's Gazette, 1982]

In order to identify the products of fer genes that act during spermiogenesis we have cloned several sperm-specific genes. This was done by preparing a library of 15-20 kb Sau3A partial fragments cloned onto lambda1059. The library was differentially screened by hybridization to cDNAs prepared to male poly A+ RNA and adult hermaphrodite poly A+ RNA. Nineteen phage were isolated that were male specific after screening 16,000 phage. Eleven of these contain genes for the major sperm protein (MSP). Most of these phage do not contain overlapping DNA fragments so the MSP must be coded for by a multi-gene family. Genes for other male specific transcripts are found on the other phage, but the gene products have not yet been identified. If we are lucky, some will be the sperm-specific proteins that we have raised anti-sera against.

Burke DJ et al. (1979) Worm Breeder's Gazette "studies on the X-chromosome of Panagrellus redivivus."

Burke DJ, Samoiloff MR, Schulz S

[Worm Breeder's Gazette, 1979]

Mutants on the X-chromosome of the dioecious Panagrellus redivivus have been isolated and mapped. Four uncs and a long have been maintained in both sexes. Paralysed, twitchers and dumpies have been obtained, but males fail to mate. Three of the uncs have reduced mobility or coordination, while the fourth unc contracts when tapped on the head, but will not reverse. The long mutant is approximately 30% longer than wild type, with no decrease in body width, Recently a new phenotype, skinny, more than 100% longer and 25% thinner has been isolated by Yvonne Jordan. The frequency of mutation using standard EMS mutagenesis of L4s is 4. 4 X 10+E-4 mutations per visible locus. The number of essential genes on the P. redivivus X-chromosome is calculated at 320 on the basis of the frequency of lethal mutations corrected for double events. The gamma-irradiation induced mutation rate is 9 X 10+E-7 mutations per locus per rad, using a dose-rate of 4.5 Kr/min. Genetically marked L2s were exposed to doses of gamma radiation varying from 5 to 150 Kr. Using target theory applied to males it was calculated that 180, 130 and 1800 X-linked genes in the total P. redivivus genome are required to complete the second, third and final moult, respectively. The kinetics of the failure of females to develop after gamma-irradiation was more indicitive of chromosome breaks rather than point mutation.

Burke DJ et al. (1982) Worm Breeder's Gazette "developmental regulation of two glyceraldehyde-3-phosphate dehydrogenases in Caenorhabditis elegans."

Burke DJ, Ward S

[Worm Breeder's Gazette, 1982]

In order to identify the products of fer genes that act during spermiogenesis we have cloned several sperm-specific genes. This was done by preparing a library of 15-20 kb Sau3A partial fragments cloned onto lambda1059. The library was differentially screened by hybridization to cDNAs prepared to male poly A+ RNA and adult hermaphrodite poly A+ RNA. Nineteen phage were isolated that were male specific after screening 16,000 phage. Eleven of these contain genes for the major sperm protein (MSP). Most of these phage do not contain overlapping DNA fragments so the MSP must be coded for by a multi gene family. Genes for other male specific transcripts are found on the other phage, but the gene products have not yet been identified. If we're lucky, some will be the sperm-specific proteins that we have raised anti sera against.

Burke DJ et al. (1983) International C. elegans Meeting "identification of sperm speicific proteins and isolation of their genes."

Ward S, Burke DJ, Kirschner B

[International C. elegans Meeting, 1983]

Burke DJ et al. (1983) International C. elegans Meeting "identification of a large multigene family encoding the major sperm protein of Caenorhabditis elegans."

Ward S, Burke DJ

[International C. elegans Meeting, 1983]

Burke DJ et al. (1983) J Mol Biol "Identification of a large multigene family encoding the major sperm protein of Caenorhabditis elegans."

Ward S, Burke DJ

[J Mol Biol, 1983]

DNA fragments corresponding to genes encoding the MSP of Caenorhabditis elegans sperm have been isolated by recombinant DNA techniques. Analyses of individual genomic clones suggest that there are multiple MSP genes that are dispersed in the genome. From restriction enzyme digests of genomic DNA fractionated and hybridized with an MSP complementary DNA probe, there appear to be more than 30 MSP genes in the genome. Despite the occurrence of this large dispersed multigene family, the MSP messenger RNA from both males and hermaphrodites is homogene in size. There are at least three different proteins of identical molecular weight but different isoelectric point that cross-react with anti-MSP antisera. Each protein is a primary translation product with no detectable post- translational modifications, suggesting that at least three of the MSP genes are expressed.

Clements CM et al. (2006) Proc Natl Acad Sci U S A "DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2."

McNally RS, Clements CM, Ting JP, Mak TW, Conti BJ

[Proc Natl Acad Sci U S A, 2006]

DJ-1/PARK7, a cancer- and Parkinson''s disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2''s subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1''s effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.

Cornejo Castro EM et al. (2010) J Neural Transm "Parkinson's disease-associated DJ-1 modulates innate immunity signaling in Caenorhabditis elegans."

Autenrieth IB, Fiesel FC, Cornejo Castro EM, Schutz M, Oberhettinger P, Springer W, Kahle PJ, Waak J, Weber SS

[J Neural Transm, 2010]

DJ-1 is a neuroprotective gene mutated in recessive Parkinson's disease (PD). In addition to direct protective functions in neurons, DJ-1 regulates neuroinflammatory signaling in primary mouse brain astrocytes. To assess the influence of DJ-1 on innate immunity signaling in vivo, we have generated djr-1 knockout Caenorhabditis elegans. When grown on pathogenic gram-negative bacteria, djr-1 (-/-) worms showed stronger phosphorylation of p38 mitogen-activated protein kinase (PMK-1) and hyper-induction of PMK-1 target genes. Thus, PD-associated DJ-1 contributes to regulation of innate immunity.

Lee JY et al. (2012) Hum Mol Genet "Human DJ-1 and its homologs are novel glyoxalases."

Lee JY, Song J, Kwon K, Park C, Baek K, Jang S, Kim C, Kim J

[Hum Mol Genet, 2012]

Human DJ-1 is a genetic cause of early-onset Parkinson's disease (PD), although its biochemical function is unknown. We report here that human DJ-1 and its homologs of the mouse and Caenorhabditis elegans are novel types of glyoxalase, converting glyoxal or methylglyoxal to glycolic or lactic acid, respectively, in the absence of glutathione. Purified DJ-1 proteins exhibit typical Michaelis-Menten kinetics, which were abolished completely in the mutants of essential catalytic residues, consisting of cysteine and glutamic acid. The presence of DJ-1 protected mouse embryonic fibroblast and dopaminergically derived SH-SY5Y cells from treatments of glyoxals. Likewise, C. elegans lacking cDJR-1.1, a DJ-1 homolog expressed primarily in the intestine, protected worms from glyoxal-induced death. Sub-lethal doses of glyoxals caused significant degeneration of the dopaminergic neurons in C. elegans lacking cDJR-1.2, another DJ-1 homolog expressed primarily in the head region, including neurons. Our findings that DJ-1 serves as scavengers for reactive carbonyl species may provide a new insight into the causation of PD.

Johnson WM et al. (2016) Biochemistry "Regulation of DJ-1 by glutaredoxin 1 in vivo - implications for Parkinson's disease."

Mieyal JJ, Lin J, Currran PL, Wilson MA, Johnson WM, Ray A, Zhu X, Gorelenkova Miller O, Choe K, Yao C, Ravindranath V, Chen SG, Milkovic NM, Wang W, Golczak M, Wilson-Delfosse AL

[Biochemistry, 2016]

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH; and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. elegans, however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx-/- mice we provide evidence that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents; and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homolog in a C. elegans in vivo model of PD. Therefore; our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.