InteractiveFly: GeneBrief

Inverted repeat binding protein 18 kDa: Biological Overview | References

Gene name - Inverted repeat binding protein 18 kDa

Synonyms -

Cytological map position - 68A6-68A6

Function - bZIP transcription factor

Keywords - Minute cell competition, arising from mutation of ribosomal proteins, requires the transcription factors Irbp18 and Xrp1 - Xrp1 forms heterodimers with Irbp18, and removal of Irbp18 also strongly suppresses the competitive elimination of Rp/+ cells in mosaic tissues - IRBP18/Xrp1 heterodimer binds sequence-specifically to its dsDNA-binding site within P-element terminal inverted repeats - both proteins are critical for repair of DNA breaks following transposase cleavage in vivo

Symbol - Irbp18

FlyBase ID: FBgn0036126

Genetic map position - chr3L:11,097,447-11,098,188

NCBI classification - Basic leucine zipper (bZIP) domain of CCAAT/enhancer-binding protein (CEBP) and similar proteins: a DNA-binding and dimerization domain

Cellular location - nuclear

NCBI links: EntrezGene, Nucleotide, Protein

Irbp18 orthologs: Biolitmine

Cell competition induces the elimination of less-fit 'loser' cells by fitter 'winner' cells. In Drosophila, cells heterozygous mutant in ribosome genes, Rp/+, known as Minutes, are outcompeted by wild-type cells. Rp/+ cells display proteotoxic stress and the oxidative stress response, which drive the loser status. Minute cell competition also requires the transcription factors Irbp18 and Xrp1, but how these contribute to the loser status is partially understood. This study provided evidence that initial proteotoxic stress in RpS3/+ cells is Xrp1-independent. However, Xrp1 is sufficient to induce proteotoxic stress in otherwise wild-type cells and is necessary for the high levels of proteotoxic stress found in RpS3/+ cells. Surprisingly, Xrp1 is also induced downstream of proteotoxic stress, and is required for the competitive elimination of cells suffering from proteotoxic stress or overexpressing Nrf2. These data suggests that a feed-forward loop between Xrp1, proteotoxic stress, and Nrf2 drives Minute cells to become losers (Langton, 2021).

Cells within a tissue may become damaged due to spontaneous or environmentally induced mutations, and it is beneficial to organismal health if these cells are removed and replaced by healthy cells. During cell competition, fitter cells, termed winners, recognise and eliminate less-fit cells, termed losers, resulting in restoration of tissue homoeostasis. Cell competition therefore promotes tissue health and is thought to provide a level of protection against developmental aberrations and against cancer by removing cells carrying oncoplastic mutations. However, an increasing body of evidence indicates that cell competition can also promote growth of established tumours, enabling them to expand at the expense of surrounding healthy cells (Langton, 2021).

Minute cell competition was discovered through the study of a class of Drosophila ribosomal mutations called Minutes and initial work suggests that it is conserved in mammals. While homozygous Rp mutations are mostly cell lethal, heterozygosity for most Rp mutations gives rise to viable adult flies that exhibit a range of phenotypes including developmental delay and shortened macrochaete bristles. Rp/+ tissues display a higher cell-autonomous death frequency than wild-type tissues, and competitive interactions further elevate cell death in Rp/+ cells bordering wild-type cells, contributing to progressive loss of Rp/+ cells over time (Langton, 2021).

It was suggested that Rp/+ cells are eliminated by cell competition due to their reduced translation rate. However, it has beem shown that Rp/+ cells experience significant proteotoxic stress and this is the main driver of their loser status. Rp/+ cells have a stoichiometric imbalance of ribosome subunits, which may provide the source of proteotoxic stress. The autophagy and proteasomal machineries become overloaded and protein aggregates build up in Rp/+ cells, leading to activation of stress pathways. This includes activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and of the oxidative stress response, whichia sufficient to cause the loser status. Restoring proteostasis in Rp/+ cells suppresses the activation of the oxidative stress response and inhibits both autonomous and competitive cell death (Langton, 2021).

Genetic screening for suppressors of cell competition led to the identification of Xrp1, a basic leucine Zipper (bZip) transcription factor. Loss of Xrp1 rescues both the reduced growth and competitive cell death of Rp/+ cells in mosaic tissues. Consistently, loss of Xrp1 restores translation rates and abolishes the increased JNK pathway activity characteristic of Rp/+ cells. Xrp1 forms heterodimers with another bZip transcription factor called Inverted repeat binding protein 18kDa (Irbp18), and removal of Irbp18 also strongly suppresses the competitive elimination of Rp/+ cells in mosaic tissues. Irbp18 and Xrp1 are transcriptionally upregulated and mutually required for each other's expression in Rp/+ cells, suggesting they function together in Minute cell competition (Blanco, 2020). Irbp18 forms heterodimers with another bZip transcription factor, ATF4 (Reinke, 2013). However, knockdown of ATF4 in Rp/+ cells reduces their survival in mosaic tissues, which is the opposite effect to knockdown of Xrp1 or Irbp18. This has been interpreted to suggest that the ATF4-Irbp18 heterodimer acts independently to the Xrp1-Irbp18 heterodimer (Langton, 2021).

How the Xrp1/Irbp18 complex contributes to the loser status is not clear. Given the recently identified role of proteotoxic stress in cell competition this study sought to establish whether Xrp1/Irbp18 and proteotoxic stress act independently or in the same pathway to contribute to cell competition in Rp/+ cells. This study identified a feed-forward loop between Xrp1/Irbp18 and proteotoxic stress, which is required for downstream activation of the oxidative stress response and the loser status. The data suggests a model in which the initial insult in RpS3/+ cells is ribosomal imbalance-induced proteotoxic stress, which is Xrp1 independent. Xrp1 is then transcriptionally activated downstream of proteotoxic stress, by increased phosphorylated-eukaryotic Initiation Factor 2α (p-eIF2α), and possibly by Nrf2. The Xrp1-Irbp18 complex then induces further proteotoxic stress, completing the feed-forward loop. This work provides new insight into the interactions between the stress signalling pathways active in Rp/+ cells and provides a mechanism for how the Xrp1-Irbp18 heterodimer mediates the competitive elimination of Rp/+ cells by wild-type cells (Langton, 2021).

This study provided evidence that a feed-forward loop between proteotoxic stress, Nrf2 and the Xrp1/Irbp18 complex is operational in RpS3/+ cells (including in the absence of cell competition) and contributes to reducing their fitness during cell competition. The data suggests that an imbalance between SSU and LSU Ribosomal proteins generates an initial source of proteotoxic stress, independently of Xrp1. This leads to xrp1 transcriptional upregulation, likely via p-eIF2α. Xrp1, together with Irbp18, generates further proteotoxic stress, in a feed-forward loop. This causes LSU ribosome proteins to accumulate, exacerbating the stoichiometric imbalance between LSU and SSU subunit components in RpS3/+ cells. Knockdown of Xrp1 or Irbp18 rescues proteotoxic stress in RpS3/+ cells, suggesting that this feed-forward loop is essential for build-up of proteotoxic stress and to reduce the competitiveness of Rp/+ cells. It is noted that during the revision of this manuscript two other independent studies have reported relevant and complementary findings. Nrf2 is also activated by proteotoxic stress and contributes to this feedback loop, either independently of p-eIF2α, or downstream of p-eIF2α. The data cannot distinguish between these two possibilities (Langton, 2021).

The data indicate that xrp1 upregulation is likely mediated by increased p-eIF2α levels. p-eIF2α accumulates in Rp/+ cells, and increasing p-eIF2α in wild-type cells (by knocking down GADD34) leads to increased xrp1 transcription, suggesting that p-eIF2α does, at least partially, contribute to xrp1 transcription in Rp/+ cells. p-eIF2α induces many transcriptional targets via stabilization of the transcription factor ATF4. This suggested that ATF4 may activate xrp1. Consistent with this, it was found that ATF4 overexpression is sufficient to upregulate an xrp1 transcriptional reporter in wing disc cells. However, it was surprising to find that xrp1 upregulation does not seem to depend on ATF4 in RpS3/+ cells. Indeed, ATF4 knockdown did not reduce xrp1 transcription in RpS3/+ cells. Furthermore, it was not possible to detect stabilization of ATF4 in RpS3/+ cells using a translational reporter. These observations suggest that p-eIF2α upregulates xrp1 transcription in Rp/+ cells by an unknown, ATF4 independent, mechanism. Alternatively, the role of ATF4 may be masked by other inputs onto the xrp1 promoter. For example, ATF4 knockdown could increase proteotoxic stress in Rp/+ cells, by inhibiting the UPR, and this may upregulate other pathways that act on the xrp1 promoter, thus masking any effect of ATF4 knockdown. This mechanism could involve Nrf2, since Nrf2 is also induced by proteotoxic stress and since it has been shown that Nrf2 induces cellular toxicity via xrp1. However, it is also possible that other factors activate Xrp1 in Rp/+ cells (Langton, 2021).

Nrf2 plays a pro-survival role in many contexts, by activating a battery of genes that enable the metabolic adaptation to oxidative stress. It is therefore counterintuitive that Nrf2 overexpression should induce the loser status and, at high expression levels, cell death. The current work suggests that the toxicity of Nrf2 is at least in part due to Xrp1 function, as elimination of Nrf2 expressing cells is rescued by Xrp1 knockdown. Whether additional Nrf2 target genes contribute to the loser status remains to be established (Langton, 2021).

Besides Xrp1 or Irbp18 knockdown, the only other condition known thus far to rescue xrp1 transcriptional upregulation in Rp/+ cells is an RpS12 point mutation, RpS1297D. However, the mechanism by which RpS12 affects xrp1 transcription remains elusive. It will be important in future work to establish whether RpS12 mutations rescue xrp1 transcriptional activation upstream or downstream of proteotoxic stress (Langton, 2021).

The results provide compelling evidence that Xrp1 and Irbp18 are responsible for inducing proteotoxic stress in RpS3/+ cells. Firstly, knockdown of Xrp1 or Irbp18 rescues the accumulation of p62 labelled aggregates and rescues the increased p-eIF2α in RpS3/+ cells. Secondly, overexpression of Xrp1 is sufficient to upregulate markers of proteotoxic stress in wild-type cells. Third, the presence of Xrp1 in RpS3/+ cells worsens the imbalance of Ribosomal proteins, causing LSUs to accumulate. It will be crucial in future work to identify the relevant targets of Xrp1 that cause proteotoxic stress in Rp/+ cells. Xrp1 may alter expression of a single target, for example a gene encoding a component or regulator of the autophagy or proteasomal systems, which deregulates cellular proteostasis. Alternatively, several target genes may contribute to enhancing proteotoxic stress: if several subunits of multi-protein complexes are deregulated by increased Xrp1, this could lead to unassembled complexes, increasing the burden on the cellular degradation machinery in already stressed Rp/+ cells. There may also be Xrp1 targets that contribute to the loser status without affecting proteotoxic stress. It is remarkable that, in addition to rescuing competitive elimination of Rp/+ cells, loss of Xrp1 can rescue elimination of mahj deficient cells and Nrf2 overexpressing cells. In mahj deficient cells, loss of Xrp1 was able to rescue the upregulation of p-eIF2α, suggesting that Xrp1 also promotes proteotoxic stress in mahj cells. It will be interesting to establish whether this is the case for Nrf2 expressing cells (Langton, 2021).

Xrp1 has been shown to play a role in a Drosophila model of Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder that can be caused by aggregogenic mutations in genes encoding RNA binding proteins, including TDP-43 and FUS, a member of the FET family of proteins. TDP-43 and FUS also form cytoplasmic, ubiquitinated aggregates, in several other neurodegenerative disorders. Drosophila cabeza (caz) is the single ortholog of the human FET proteins. Xrp1 is upregulated in caz mutants, and the pupal lethality, motor defects and dysregulated gene expression of caz mutants is rescued by xrp1 heterozygosity [51]. Therefore, it is possible that the feed-forward loop that this study has uncovered is also active in this context: formation of cytoplasmic proteotoxic aggregates could stimulate xrp1 expression, which could then induce further proteotoxic stress in a feed forward loop, resulting in neuronal toxicity. Understanding the relationship between Xrp1, proteotoxic stress and oxidative stress may thus be beneficial for the study of human proteinopathies (Langton, 2021).

Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila

Reduced copy number of ribosomal protein (Rp) genes adversely affects both flies and mammals. Xrp1 encodes a reportedly Drosophila-specific AT-hook, bZIP protein responsible for many of the effects including the elimination of Rp mutant cells by competition with wild type cells. Irbp18, an evolutionarily conserved bZIP gene, heterodimerizes with Xrp1 and with another bZip protein, dATF4. This study shows that Irbp18 is required for the effects of Xrp1, whereas dATF4 does not share the same phenotype, indicating that Xrp1/Irbp18 is the complex active in Rp mutant cells, independently of other complexes that share Irbp18. Xrp1 and Irbp18 transcripts and proteins are upregulated in Rp mutant cells by auto-regulatory expression that depends on the Xrp1 DNA binding domains and is necessary for cell competition. Xrp1 is conserved beyond Drosophila, although under positive selection for rapid evolution, and that at least one human bZip protein can similarly affect Drosophila development (Blanco, 2020).

Heterozygous mutation of ribosomal protein genes lead to cell-autonomous, deleterious phenotypes in both flies and mammals and provide the classic example of a genotype that is eliminated from mosaics by competition. There is increasing interest in the potential roles of cell competition in mammalian development, cancer development, and in regenerative medicine. A remarkable recent finding from Drosophila is that many of the phenotypic effects of mutating ribosomal protein genes are mediated by a putative transcription factor, Xrp1, rather than as a direct consequence of altered ribosome number. Accordingly, Xrp1 plays a key role in the elimination of Rp mutant cells by cell competition. Xrp1 transcription and protein expression are elevated in Rp mutant cells, restricting translation, cellular growth rate, and the rate of organismal development, and enabling cell competition with nearby wild type cells. Xrp1 had previously been implicated in the DNA damage response downstream of p53 and in the transposition of P elements, and contributes to the pathology of a Drosophila model of Amyotrophic Lateral Sclerosis, as well as to the coordination of organ growth in flies with Rp gene knockdowns (Blanco, 2020).

Xrp1 has been reported not to have homologs in other eukaryotes. This seems surprising given the highly conserved and fundamental roles of ribosomal proteins, and is a barrier to investigating the potential conservation of cell competition mechanisms and the roles of cell competition in mammals, for example in the development of cancer. Xrp1 binds to DNA as a heterodimer with Irbp18, the Drosophila homolog of the C/EBP protein family, which is a conserved protein and co-purifies with it in cultured cells. Irbp18 in turn heterodimerizes with the conserved protein dATF4, encoded by the crc gene in Drosophila). This led to an investigation od whether it is the Xrp1 heterodimer with the conserved Irbp18 protein that functions in Rp+/- cells, and if so whether Xrp1/Irbp18 acts positively; alternatively, Xrp1 could act as a competitive inhibitor of Irbp18 function with its other partner, dAtf4/Crc, in which case Xrp1 could represent a Drosophila-specific regulator of a more conserved pathway (Blanco, 2020).

The current data provide overwhelming genetic evidence that Xrp1 does function along with Irbp18. Like Xrp1 mutations, irbp18 mutation suppressed multiple effects of Rp mutations, including the elimination of Rp+/- mutant cells by competitive apoptosis in the proximity of wild type cells and the reduced growth of Rp+/- wing cells. Like Xrp1, irbp18 was also required for the prompt disappearance of Rp-/- cell clones, which survived in the irbp18 mutant background. All these data were consistent with the model that Xrp1/Irbp18 heterodimers are the active species in Rp mutant cells and were inconsistent with the idea that Xrp1 might act as a competitive inhibitor of other Irbp18-containing species, as this would have predicted that Irb18 mutations would have had phenotypes opposite to those of Xrp1 (Blanco, 2020).

The phenotype of Crc knockdown is different from those of Xrp1 and irbp18 mutations. Whereas Xrp1 and irbp18 mutations enhance the growth and competitiveness of Rp+/- cells, crc knockdown greatly diminished growth and survival of Rp+/- cells. If Xrp1 was a Drosophila-specific competitive inhibitor of a conserved Crc/Irbp18 heterodimer that was required for growth, both irbp18 and crc mutants would show reduced growth, similar to Rp+/- genotypes. In contrast to this, irbp18 mutants have little phenotype except in Rp+/- genotypes, where their effects closely resemble those of Xrp1 mutants. Also, whereas crc knockdown strongly and cell-autonomously affected the growth of Rp+/- cells, it had less effect on Rp+/+ cells (Blanco, 2020).

In addition to these findings in loss-of-function experiments, it was also found that Xrp1 over-expression phenotypes depended on IRBP18, as would be expected if these proteins function together. It was also found that Xrp1 over-expression at higher temperatures resulted in a still stronger eye phenotype where simultaneous irbp18 mutation restored normal eye size but did not completely restore eye morphology. This is consistent with some IRBP18-independent component to ectopic Xrp1 function that is either cold-sensitive or only apparent at the highest ectopic expression levels. There is not yet any evidence whether these over-expression effects are physiologically relevant (Blanco, 2020).

Taken together, these findings suggest that the Xrp1/IRBP18 and Crc/IRBP18 heterodimers have independent and perhaps unrelated functions. Consistent with this, ectopic expression of IRBP18 had no phenotypic effect, suggesting that IRBP18 is normally made in excess, so that it is Xrp1 that is limiting for the growth inhibiting activities of the Xrp1/IRBP18 heterodimers, which do not impact IRBP18 availability sufficiently to affect Crc/Irbp18 functions (Blanco, 2020).

As expected if Xrp1 functions in a heterodimer, the basic and Leucine Zipper domains were important for Xrp1 function, as was the AT hook. In over-expression assays only, there could be reduced activity of proteins deleted for any of these domains individually, but not of a truncation that precedes them all. When encoded from the endogenous locus, basic and AT-hook domains appeared absolutely required (Blanco, 2020).

Mutual auto-regulation may be a significant feature of Xrp1 and IRBP18 function. As noted previously, the elevated Xrp1 and irbp18 transcription observed in Rp+/- wing discs is dependent on Xrp1 function. This study shows that IRBP18 protein levels are also elevated in Rp+/- cells in an Xrp1-dependent fashion, and that irbp18 is also required for the autoregulation. In principle, autoregulation could have been the major or indeed the only transcriptional function of the Xrp1/IRBP18 heterodimer, ie perhaps these proteins could control cell competition through other mechanisms once levels were sufficient. This cannot be completely correct, however, because Xrp1 was still substantially dependent on the irbp18 gene and on the Leucine Zipper and DNA binding domains when expressed using GAL4-driven transgenes that are independent of auto-regulation, so by-passing the requirement of auto-regulation does not relieve the requirements for heterodimerization and DNA binding domains. It is also worth noting that Xrp1 and irbp18 are both required to promptly eliminate Rp-/- cells, where their expression does not require auto-regulation. Although implicating other transcriptional targets of Xrp1/IRBP18 in Rp+/- and Rp-/- cells, these studies do not rule out other functions besides transcription (Blanco, 2020).

Previously it was thought that Xrp1 was restricted to the genus Drosophila, a surprising finding for a protein that has an important cellular function. This study found, however, that Xrp1 genes have been under strong positive selection for rapid evolutionary change. Recurrent positive selection is often the sign of an evolutionary arms race, such as are often driven by host-pathogen interactions, sexual competition, or intra-genomic conflict. Possibly pathogens target Xrp1 to promote growth and survival of infected cells. It is interesting that Xrp1 is already documented to interact with one transposable element, the P element. However, none of these scenarios for positive selection, or indeed additional possibilities, can yet be ruled out (Blanco, 2020).

Rapid divergence makes homology difficult to detect, and accordingly this study has identify divergent Xrp1 homologs in other Dipteran insects that have not previously been annotated because their sequence similarities are restricted to the key DNA-binding portion of the protein, and to a more amino-terminal Xrp1-homology domain. The failure to identify still more distant homologs might be genuine, or might reflect further divergence beyond ones ability to recognize homology. Mammals do contain other members of the C/EBP protein family without identified Drosophila homologs, and this study shows that DDIT3 (aka CHOP and C/EBP-Z) can generate a similar phenotype to Xrp1 when expressed in Drosophila. Interestingly C/EBP-α, one of the mammalian proteins more related to Irbp18, has been implicated in a cell competition-like phenomenon, the elimination of cells from the multipotent hematopoietic stem cell niche following irradiation (Blanco, 2020).

Drosophila IRBP bZIP heterodimer binds P-element DNA and affects hybrid dysgenesis

In Drosophila, P-element transposition causes mutagenesis and genome instability during hybrid dysgenesis. The P-element 31-bp terminal inverted repeats (TIRs) contain sequences essential for transposase cleavage and have been implicated in DNA repair via protein-DNA interactions with cellular proteins. The identity and function of these cellular proteins were unknown. Biochemical characterization of proteins that bind the TIRs identified a heterodimeric basic leucine zipper (bZIP) complex between an uncharacterized protein that is termed 'Inverted Repeat Binding Protein (IRBP) 18 and its partner Xrp1. The reconstituted IRBP18/Xrp1 heterodimer binds sequence-specifically to its dsDNA-binding site within the P-element TIRs. Genetic analyses implicate both proteins as critical for repair of DNA breaks following transposase cleavage in vivo. These results identify a cellular protein complex that binds an active mobile element and plays a more general role in maintaining genome stability (Francis, 2016).

A role for the IRBP complex in the P-element transposition reaction has been postulated since initial identification of its sequence-specific DNA-binding properties. The organizational overlap between IRBP DNA binding and transposase cleavage sites makes the IRBP complex a prime cellular candidate to influence some aspect of the P-element transposition cycle. Several putative IRBP proteins copurified with observed IRBP DNA-binding activity or unambiguously promoted DNA repair posttransposase P-element cleavage (Ku 70 and mus309/DmBLM). None, however, could reconstitute site-specific DNA binding to the P-element 31-bp TIRs (Francis, 2016).

This report identifies a bZIP heterodimer between a C/EBP family member IRBP18 and a drosophilid-specific protein Xrp1 as the sequence-specific DNA-binding subunits of a larger multiprotein IRBP complex that binds to the P-element TIRs. These proteins work in concert to facilitate efficient DNA repair following P-element transposase-mediated DNA cleavage. Finally, these proteins are required more generally in the cellular DNA damage response and DSB repair in the absence of P elements (Francis, 2016).

Repair of P-element~induced DNA breaks occurs predominantly through two distinct DSB repair pathways: Non-homologous end joining (NHEJ) or a variant of classical homologous recombinational repair, synthesis-dependent strand annealing (SDSA), The choice between these two pathways is dictated by cell-cycle location, the availability of pathway substrates, and tissue type. Because the IRBP homozygous mutant males are sterile, it is not possible at present to use any of the established DNA repair reporter strains to determine in which DNA repair pathway IRBP18 and Xrp1 participates. Future would should determine if the IRBP18/Xrp1 heterodimer can bind directly to different DNA repair intermediates and thus provide a direct link between the bZIP heterodimer and DNA repair (Francis, 2016).

A role for bZIP proteins and specifically mammalian C/EBP proteins in DNA repair is well established. In human and mouse keratinocytes, UV-B UV DNA damage induces p53-dependent transcriptional activation of both the C/EBPα and β genes. C/EBPα expressed in prostate cancer cells where it interacts with the DNA repair proteins Ku p70/p80 heterodimer and the poly (ADP ribose) polymerase 1 (PARP-1). Notably, Drosophila p53 up-regulates three bZIP proteins (CG6272/IRBP18, CG17836/Xrp1, and CG15479/Mabiki) upon DNA damage. CG15479/Mabiki is a novel regulator of caspase-independent cell death of excess cells in the expanded head region of 6x-bcd embryos and is thought to work in concert with other caspase-independent cell death mechanisms to ensure proper development. Genetic deletion of the CG17836/Xrp1 gene resulted in a DNA repair phenotype when challenged with ionizing radiation. Additionally, the Dmp53 DNA damage-induced apoptotic response was unaffected in the Xrp1 mutants, suggesting that Xrp1 functions to preserve genome stability through a pathway independent of apoptosis. Although this study has demonstrated that IRBP18 and Xrp1 share a similar function in DNA repair, more experiments are needed to understand how these proteins work downstream of p53 transactivation (Francis, 2016).

D. melanogaster uses multiple endogenous mechanisms to limit P-element transposition. Expression of catalytically active transposase is restricted to the germline by tissue-specific pre-mRNA splicing regulation. The germline piwi-interacting RNA pathway has been demonstrated to repress transposition in trans and plays a critical role in host adaptation to newly invaded P elements. It is proposed that the IRBP18/Xrp1 heterodimer recognizes new P elements and that its native function is to facilitate repair of breaks to maintain genomic stability during a genotoxic event such as ionizing radiation or the massive P-element mobilization that occurs following a hybrid dysgenic cross (Francis, 2016).

bZIP proteins are well suited to recognize newly invaded foreign DNA due to their inherit ability to form multiple heterodimers. IRBP18 and Xrp1, for example, form heterodimers with other several other bZIP proteins; the net result is expansion of the repertoire of DNA sequences that can be bound. This library of bZIP dimers can be deployed to recognize foreign DNA as part of a survival mechanism against the genome instability created by foreign DNA invasion. In humans, mice and Drosophila p53 transactivate steady-state levels of several bZIP proteins in response to DNA damage. It is unclear how changes in steady-state levels of these DNA repair proteins determine dimer formation or function. What is clear is that bZIP proteins are important players in DNA repair and maintenance of genome stability. In this respect, the IRBP18/Xrp1 heterodimer is a newly identified component of the interconnected pathways to combat the genotoxic effects of mass invasion/mobilization of transposons (Francis, 2016).


Search PubMed for articles about Drosophila Irbp18

Blanco, J., Cooper, J. C. and Baker, N. E. (2020). Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila. Elife 9. PubMed ID: 31909714

Francis, M. J., Roche, S., Cho, M. J., Beall, E., Min, B., Panganiban, R. P. and Rio, D. C. (2016). Drosophila IRBP bZIP heterodimer binds P-element DNA and affects hybrid dysgenesis. Proc Natl Acad Sci U S A 113(46): 13003-13008. PubMed ID: 27799520

Langton, P. F., Baumgartner, M. E., Logeay, R. and Piddini, E. (2021). Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status. PLoS Genet 17(12): e1009946. PubMed ID: 34914692

Reinke, A. W., Baek, J., Ashenberg, O. and Keating, A. E. (2013). Networks of bZIP protein-protein interactions diversified over a billion years of evolution. Science 340(6133): 730-734. PubMed ID: 23661758

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date revised: 5 July 2022

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