“Draft:GFZF”的意思、由来-开放百科全书

GFZF (GST-containing FLYWCH Zinc Finger protein) is a Glutathione SH-transferase (GST) containing protein identified in Drosophila Melanogaster^[1]. GFZF is a 1045 amino acid protein that possesses a zinc finger domain with a tandem array of four FLYWCH zinc finger motifs at its N-terminus, and the C-terminal domain shares a 46% homology with GST^[1]. The gene that encodes GFZF maps to chromosome 3 at position 84C6^[1]. In addition to being expressed through all stages of fly embryonic development, it localizes to the cytoplasm of fly cells^[1]. Although the exact function of the FLYWCH motif is unknown, it is found in the chromatin associated Mod (mdg4) proteins that are part of the gypsy silencing complex^[2]. GFZF has additionally been identified in screens for factors involved in transcriptional regulation, cell cycle regulation^[3], DNA damage checkpoints^[4], oxidative stress responses^[5], control of RAS/mitogen-activated protein kinase (MAPK) signaling, organization of polycomb sequences^[6], and speciation^[7].

Role in Cell Cycle Regulation

GFZF has been shown to play a key role in cell cycle regulation in D. melanogaster, supported by a genome-wide RNA interference screen looking to identify G2/M checkpoint genes in Drosophila cells in which GFZF was a significant target of interest^[4]. GFZF critically may respond to DNA damage by blocking cell proliferation through the dE2F2/RBF pathway^[3]. Furthermore, GFZF can be a positive regulator of cell growth. Most notably, the GFZF transcriptionally regulates the Ras pathway, evidenced by the suppression of Ras phenotypes by loss-of-function alleles as GFZF^[8].

The ability of GFZF to regulate cell cycle progression may be the reason for hybrid male inviabiilty in D. melanogaster and D. simulans hybrids, because these hybrid males display canonical cell cycle progression defects such as death at the late larval stage and degenerate imaginal discs^[9]. This experiment suggests that a role of the D. simulans homolog of GFZF is to suppress proliferation on imaginal discs^[10], preventing larvae from moving towards pupation. Additional GFZF^sim knockdown experiments rescued the cell proliferation phenotype, namely proliferating S-phase cells, further supporting this hypothesis^[10].

Mechanism of Action

Interaction between GFZF and MBP1

Cells coordinate processes required for survival and development through regulating RNA polymerase II-transcribed genes through transcription elements that bind to promoter regions^[11]. One major element, Motif 1^[12]^[13], is present in promoter regions of numerous Drosophila genes. M1BP is a factor that binds to thousands of genes, and M1BP-bound promoters tend to lack many elements canonically thought to be necessary for initiation, such as the TATA box^[12]. GFZF is recruited by M1BP to promoters, and is a transcriptional coactivator with GST activity^[1]. While GSTs have traditionally been studied for their role in cellular detoxification, they have also been implicated in signal transduction regulation^[14], apoptosis inhibition^[15], and oxidative stress responses^[16].

Chromosomal Localization of GFZF

Although older literature characterized GFZF as a primarily cytoplasmic protein^[1], recent immunofluorescence microscopy experiments with fluorescent anti-GFZF antibodies have suggested that GFZF associates with chromosomes^[17]. Both MBP1 and GFZF have similar localization patterns, supporting their co-localization at a variety of promoters^[17]. Chromatin immunoprecipitation with exonuclease (ChIP-exo) confirmed that MBP1 and GFZF colocalize at many promoters^[17]. To regulate cell cycle progression, GFZF associates with 22 out of 64 genes involved in the G2/M DNA damage checkpoint^[17], including promoters of relevant factors (myt1, 140303e, and tefu)^[4], thus controlling progression.

GST Functionality

Unusually, GFZF is a combination of zinc fingers and a GST domain^[17]. This property was first discovered when it was observed to be able to bind to glutathione sepharose beads^[1]. Mutations in the GST domain cause larval lethality, indicating its necessity for survival^[17]. While not fully characterized, the GST activity can be important for gene expression – as GSTs generally protect cells from toxic native and foreign compounds^[18], the GST domain may inhibit DNA damage at promoters. There is additionally evidence that the GST transcription factor can sense the redox state of the cell and allow cells to alter transcription or inhibit cell cycle progression in response to stressors^[19].

A protein that suggests of GST-mediated regulated of cell events is Brf2. Brf2 a transcription factor that has a cysteine residue that, when oxidized, inhibits Brf2’s ability to bind to the TATA binding protein^[20]. Furthermore, a small amount of hydrogen peroxide reduces the activity of Pol II in promoter-adjacent regions of genes^[21]. Last, PrfA is a protein in pathogenic bacteria Listeria monocytogenes that is allosterically regulated by glutathione^[22] – these intracellular control mechanisms may regulate GFZF function in response to chemical stressors, allowing for rapid cell cycle regulation and other downstream responses.

Control of MAPK Signaling

GFZF is respond for modulating mek, an upstream effector of MAPK, and PTP-ER expression via mRNA processing factors^[8]. Upon GFZF knockdown, researchers observed a strong reduction in mek transcript levels, and the RASv12-induced hemocyte proliferation phenotype was substantially reduced, indicating that it may be acting as a positive transcription factor^[8]. Alternatively, because FLYWCH domain proteins can repress miRNA expression in C. elegans, GFZF may be repressing the production of miRNA that targets mek transcripts^[8]. By adding this extra dimension of regulatory control to the Ras/MAPK signaling pathway, GFZF may be an important regulatory element for downstream MAPK-dependent events.

Within-Species Incompatibility

GFZF plays an important role in hybrid inviability^[7]^[10]. Prune mutant D. melanogaster females crossed to males from a certain wild type Killer-of-prune strain cause inviable resulting male offspring^[10]. Prune is an X-linked eye color gene, and Killer-of-prune (Kpn) is a single non-synonymous change in the awd gene^[23]. Kpn is only lethal in combination with the prune mutation, but is rescued with the mutation of GFZF, as identified in a comprehensive genetic screen discover suppressors of this interaction^[10]. There may be a few essential signaling pathways for dominant lethal interactions, as the screen isolated a total of 13 mutants that rescued viability and all mapped to GFZF^[10].

References

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