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P32: Biological Overview | References

BIOLOGICAL OVERVIEW

Nuclear DNA in the male gamete of sexually reproducing animals is organized as sperm chromatin compacted primarily by sperm-specific protamines. Fertilization leads to sperm chromatin remodeling, during which protamines are expelled and replaced by histones. Despite increased understanding of the factors that mediate nucleosome assembly in the nascent male pronucleus, the machinery for protamine removal remains largely unknown. This study identified four Drosophila protamine chaperones that mediate the dissociation of protamine-DNA complexes: NAP-1, NLP, and nucleophosmin are previously characterized histone chaperones, and TAP/p32 has no known function in chromatin metabolism. This study showed TAP/p32 to be required for the removal of Drosophila protamine B in vitro, whereas NAP-1, NLP, and Nph share roles in the removal of protamine A. Embryos from P32-null females show defective formation of the male pronucleus in vivo. TAP/p32, similar to NAP-1, NLP, and Nph, facilitates nucleosome assembly in vitro and is therefore a histone chaperone. Furthermore, mutants of P32, Nlp, and Nph exhibit synthetic-lethal genetic interactions. In summary, this study identified factors mediating protamine removal from DNA and reconstituted in a defined system the process of sperm chromatin remodeling that exchanges protamines for histones to form the nucleosome-based chromatin characteristic of somatic cells (Emelyanov, 2014).

The DNA of metazoan somatic cells is packaged into a compact nucleoprotein complex termed chromatin. Chromatin fiber is comprised of highly conserved repetitive units (nucleosomes) that contain an octamer of four core histones and 145-147 base pairs (bp) of DNA wrapped around the octamer in 1.65 turns of a left-handed superhelix. Nucleosomes are assembled in vivo in an ATP-dependent fashion through a concerted and sequential action of core histone chaperones and motor proteins that belong to the Snf2 family of DNA-dependent ATPases. For instance, Drosophila ACF/CHRAC can mediate chromatin assembly in conjunction with histone chaperone NAP-1. Other known ATP-dependent chromatin assembly factors include RSF, CHD1, ATRX, and ToRC/NoRC (Emelyanov, 2014).

The most abundant chromatin component in male germline cells is protamines-small positively charged arginine- and cysteine-rich protein. During spermiogenesis, protamines replace 85%-95% of DNA-bound histones in the nucleus to achieve a higher density of sperm nuclear DNA. Crystalline-like sperm chromatin structure is sixfold more compact than metaphase chromosomes and renders sperm DNA enzymatically inert. At fertilization, the oocyte remodels the condensed sperm chromatin into a transcriptionally competent chromatin of the male pronucleus. During this process, protamines are expelled and replaced with oocyte-supplied histones, which are then organized into nucleosomes. Sperm chromatin remodeling (SCR) is controlled by biochemical activities in the early oocyte, but components of these activities remain largely unknown. However various protein factors have been implicated in SCR, including core histone chaperones from Xenopus and Drosophila (NAP-1, p22, DF31, HIRA, and Yemanuclein). In mammals, members of nucleoplasmin/nucleophosmin family proteins (NPM1-3) function in sperm chromatin decondensation in vitro. In addition, Npm2 knockout female mice exhibit fertility defects consistent with a role of NPM2 in nuclear and nucleolar chromatin organization. It was also suggested that sperm chromatin decondensation is ATP-dependent (Emelyanov, 2014).

Drosophila sperm cells contain two major protamines (A and B) encoded by male-specific transcripts Mst35Ba and Mst35Bb, respectively. The Drosophila maternal effect mutant sésame (ssm) prevents male pronucleus formation. ssm encodes the histone variant H3.3-specific chaperone HIRA, postulated to be required for replication-independent deposition of histones in the male pronucleus during sperm decondensation . In eggs from homozygous ssm females, maternal histones are not deposited in the chromatin of male pronuclei, preventing normal mitosis and resulting in the development of gynogenetic haploid embryos and embryonic stage lethality. A similar phenotype is observed in null mutants of the gene encoding ATP-dependent chromatin assembly factor CHD1. Thus, CHD1 and HIRA act cooperatively and are required for nucleosome assembly during SCR. Intriguingly, protamines are efficiently expelled from the DNA of nascent male pronuclei in Chd1 and ssm eggs, suggesting that protamine removal and histone deposition are functionally distinct steps (Emelyanov, 2014).

This study used a biochemical approach to identify specific protein components of the Drosophila egg machinery that promote the dissociation of protamine-DNA complexes of sperm chromatin. These factors turn out to be two known core histone chaperones (NAP-1 and NLP), a homolog of mammalian nucleophosmin, and a novel Drosophila histone chaperone (TAP/p32). These putative 'protamine chaperones' facilitate SCR independently of CHD1 and HIRA, which mediate nucleosome assembly in nascent male pronuclei. Of note, TAP/p32 is specifically required to expel Drosophila protamine B from sperm chromatin in vitro, whereas NAP-1, NLP, and nucleophosmin share roles in removal of protamine A. In vivo evidence is provided that TAP/p32 functions in Drosophila egg SCR. In conclusion, this study has characterized protein factors that mediate the first obligatory step of SCR (protamine dissociation) and reconstituted the complete SCR reaction (reorganization of protamine-containing sperm chromatin into core histone-containing nucleosome arrays) in a purified defined system in vitro (Emelyanov, 2014).

Although recent studies provide details of sperm chromatin composition (Hammoud 2009; Miller 2010) and assembly during spermiogenesis (Rathke 2014), relatively little is known about the protein machinery that mediates SCR during fertilization (Orsi, 2013). In vivo analyses in Drosophila suggest that removal of protamines from sperm chromatin is biochemically uncoupled from subsequent nucleosome assembly because male pronucleus-specific nucleosome assembly factors CHD1 and HIRA are not required for protamine removal. This study demonstrates that, indeed, a separate set of protein factors (protamine chaperones) is required for protamine eviction. Using assay-based biochemical approaches, four Drosophila proteins were identified that are sufficient for unraveling of DNA-protamine complexes in vitro. Their biochemical activities and mechanisms of SCR were analyzed. Significantly, it was possible to recapitulate the entire process of SCR (protamine eviction and nucleosome assembly) in a defined purified system. Biological functions of TAP/p32 were further analyzed in Drosophila, and evidence was obtained of its proposed roles in SCR in vivo. Finally, it was discovered that all four proteins additionally share a function as core histone chaperones (Emelyanov, 2014).

Recent microarray analysis of mating-responsive genes in Drosophila revealed that CG6459/P32 expression is strongly activated in the female lower reproductive tract within 6 h of mating. In fact, CG6459/P32 exhibits the strongest response of all genes identified in the study. The up-regulation is transient and is reversed 24 h after mating. This temporal expression pattern of TAP/p32 further supports its proposed role during fertilization (Emelyanov, 2014).

Intriguingly, orthologs of protamine chaperones are expressed in unicellular organisms, such as S. cerevisiae, which do not express protamines and whose gametes do not undergo the chromatin reorganization characteristic of metazoan sperm cells. Evidence is provided that Mam33p, an S. cerevisiae ortholog of TAP/p32, is involved in chromatin remodeling and DNA compaction and/or repair. It is likely that protamine chaperone homologs in unicellular eukaryotes perform conserved functions of core histone chaperones and are involved in nucleosome assembly and remodeling. During metazoan evolution, however, their biochemical activities may have been harnessed for SCR owing to biochemical similarities (net charge and amino acid composition) and functional roles (DNA compaction) of histones and protamines (Emelyanov, 2014).

Although yeast TAP/p32 ortholog Mam33p is clearly involved in regulation of DNA integrity/repair in response to treatment with mutagens and genetically interacts with factors of chromatin remodeling and DNA compaction and repair, it is also required for metabolism of alternative carbon sources. Similarly, mammalian TAP/p32 has also been implicated in mitochondrial function. Furthermore, Drosophila TAP/p32 and NAP-1, although subject to nuclear translocation, are also efficiently recruited to mitochondria. Hence, it is interesting to consider the apparent dual role of TAP/p32 in mitochondrial function and nuclear DNA compaction. Mature sperm cells in Drosophila and vertebrates contain a stack of mitochondrial structures in the midpiece at the junction of the head and tail. (In Drosophila, the sperm mitochondria are depleted of DNA, and, in most metazoan species during fertilization, sperm mitochondria undergo rapid ubiquitination and degradation by autophagocytosis) Thus, the elevated affinity of TAP/p32 and NAP-1 to protein components of mitochondria may be used and adapted for rapid and specific recruitment of the TAP/p32 and NAP-1 to the sperm head, which would facilitate their loading onto sperm chromatin for its processing (Emelyanov, 2014).

It has been suggested that Xenopus nucleoplasmin is sufficient for the initial stage of SCR (decondensation of demembranated sperm and removal of sperm basic proteins SP1-6 in vitro). However, the removal of sperm proteins (and their replacement by histones) in the presence of nucleoplasmin does not appear complete/quantitative. Furthermore, the Xenopus sperm decondensation assay is prone to artifacts: It is frequently performed (and works) with heterologous proteins and extracts, including those from yeast. In contrast, the current analyses suggest that a family of several factors may share partially redundant roles in protamine removal, and their cooperative action is necessary and sufficient for complete protamine eviction from sperm chromatin substrates. On the other hand, considering poor evolutionary conservation of protamine number and identities, it is possible that species other than Drosophila use smaller or larger sets of factors for SCR (Emelyanov, 2014).

Despite being ~94% identical, protamines A and B require different chaperones for their removal. For instance, in the absence of TAP/p32, a mixture of NAP-1, NLP, and Nph is incapable of protamine B eviction. Protamine polypeptides are extremely evolutionarily divergent. In fact, it is rarely possible to assign a protamine function based on a sequence conservation search of related proteins in distinct metazoan species. For example, a closely related organism, Drosophila simulans, expresses one protein homologous to D. melanogaster protamines. It is more closely related to protamine B and shares with it only 77% identity. D. simulans also express orthologs of protamine chaperones. A high degree of functional/sequence specificity makes it unlikely that D. melanogaster protamine chaperones will be able to remodel MSC assembled from more divergent, evolutionarily distant protamines. This specificity may contribute to gametic isolation of distinct species. In the future, it will be interesting to analyze cross-reactivity of protamines and protamine chaperones from these species in MSC remodeling in vitro and in vivo (Emelyanov, 2014).

Thioredoxin-dependent disulfide bond reduction is required for protamine eviction from sperm chromatin

Cysteine oxidation in protamines leads to their oligomerization and contributes to sperm chromatin compaction. This study identifies the Drosophila thioredoxin Deadhead (DHD) as the factor responsible for the reduction of intermolecular disulfide bonds in protamines and their eviction from sperm during fertilization. Protamine chaperone TAP/p32 dissociates DNA-protamine complexes in vitro only when protamine oligomers are first converted to monomers by DHD. dhd-null embryos cannot decondense sperm chromatin and terminate development after the first pronuclear division. Therefore, the thioredoxin DHD plays a critical role in early development to facilitate the switch from protamine-based sperm chromatin structures to the somatic nucleosomal chromatin (Emelyanov, 2016).

The amorphic mutant of Drosophila deadhead (dhd) has been described. dhd is not essential for adult viability but is recessive maternal effect lethal: The majority of eggs laid by homozygous females is fertilized but fails to initiate development. To test whether DHD affects sperm decondensation and protamine eviction, homozygous dhd mothers were crossed with fathers that carry transgenes expressing eGFP-tagged ProtB and don juan (dj) that encode the major components of sperm heads and tails, respectively. Heterozygous dhd/FM7 mothers were used in control crosses. dhd embryos were completely incapable of processing sperm chromatin. Microscopic analyses revealed that the majority of 0- to 4-h embryos (>60% of the total scored) was fertilized and contained GFP-labeled sperm. Importantly, they failed to remove Prot B from sperm heads, which remained fully compacted. In most of the embryos (~55% of the total), the female pronuclei underwent one haploid mitosis but terminated further divisions. The sperm heads did not specifically migrate to the middle of the embryo but rather assumed random positions within the egg. In contrast, dhd/FM7 embryos did not exhibit any developmental defects. Also, no Prot B-eGFP-labeled sperm heads were observed after inspecting >2000 fertilized heterozygous embryos, consistent with an extremely fast (within minutes and, frequently, before egg deposition) sperm decondensation and protamine eviction during normal development (Emelyanov, 2016).

Occasionally, dhd/dhd embryos (~5% of the total) entered syncytial divisions but aborted their development prior to cellularization. Although persistent sperm cells were not detected in these syncytial embryos, other evidence indicated that they did not remodel sperm chromatin or form the male pronucleus. First, the appearance of anaphase chromosomes suggested a haploid DNA content. Furthermore, PCR analyses of maternal- and paternal-derived sequences in the genomic DNA of dhd embryos exposed a very strong overabundance of maternal DNA. The aborted development of gynogenetic haploid embryos in the dhd mutant is similar to that in mutants of ssm, yem, and Chd1, which encode the HIRA-YEM complex and CHD1, the factors required for nucleosome assembly in the male pronucleus. However, in contrast to dhd mutation, ssm, yem, and Chd1 mutations lead to the vast majority of embryos entering haploid syncytial divisions. Therefore, although DHD is clearly required for sperm chromatin remodeling in vivo, it may also be involved in other embryonic functions, such as regulation of DNA synthesis or S-phase initiation during preblastoderm mitosis, as proposed previously (Emelyanov, 2016).

In metazoan development, nuclear DNA undergoes dramatic differentiation-dependent, activity-dependent, and cell cycle-dependent transitions that alter the composition, distribution, and modification status of associated proteins. This study demonstrates that Drosophila sperm chromatin compaction involves oligomerization of protamines via intermolecular disulfide bridges. To convert the condensed, static, and metabolically inert paternal chromatin into a transcriptionally and otherwise enzymatically competent somatic cell chromatin, the embryo expresses a network of specialized proteins, which includes the thioredoxin DHD and protamine chaperones. Synergistically, they reverse the protamine oligomerization and remove them from DNA during fertilization. This network of physically interacting proteins plays an essential role in early embryonic development. Metazoans exhibit a strong similarity in amino acid content (cysteine enrichment) and secondary structure of protamines (intramolecular and intermolecular disulfide bonds) as well as primary structures of protamine chaperones and various thioredoxins. Thus, the function of the thioredoxin system in sperm chromatin remodeling is likely conserved in evolution (Emelyanov, 2016).

Genetic analysis in Drosophila reveals a role for the mitochondrial protein p32 in synaptic transmission

Mitochondria located within neuronal presynaptic terminals have been shown to play important roles in the release of chemical neurotransmitters. In the present study, a genetic screen for synaptic transmission mutants of Drosophila has identified the first mutation in a Drosophila homolog of the mitochondrial protein P32. Although P32 is highly conserved and has been studied extensively, its physiological role in mitochondria remains unknown and it has not previously been implicated in neural function. The Drosophila P32 mutant, referred to as dp32^EC1, exhibited a temperature-sensitive (TS) paralytic behavioral phenotype. Moreover, electrophysiological analysis at adult neuromuscular synapses revealed a TS reduction in the amplitude of excitatory postsynaptic currents (EPSC) and indicated that dP32 functions in neurotransmitter release. These studies are the first to address P32 function in Drosophila and expand the knowledge of mitochondrial proteins contributing to synaptic transmission (Lutas, 2012).

A genetic screen for synaptic transmission mutants in Drosophila isolated a new mutation in a Drosophila homolog of the mitochondrial protein P32, which represents the first P32 mutation in a multicellular organism. Although P32 is highly conserved and has been studied extensively, its physiological function in mitochondria remains unknown. This new mutant, referred to as dP32^EC1, exhibited a temperature-sensitive (TS) paralytic behavioral phenotype. Moreover, electrophysiological analysis at adult neuromuscular synapses revealed a TS reduction in neurotransmitter release, indicating that dP32 serves an important function in synaptic transmission. Immunocytochemical analysis has shown that dP32 is located within presynaptic mitochondria, which are known to be important in ATP production and calcium signaling at synapses. Furthermore, the basic molecular and structural organization of synapses appears to be normal in the dP32 mutant, suggesting a direct role for this protein in synaptic function. At the molecular level, biochemical studies indicated conserved homomultimeric interactions of dP32 subunits. Finally, assessment of presynaptic mitochondrial function was examined in the dP32 mutant through measurement of ATP levels and imaging studies of mitochondrial membrane potential and presynaptic calcium. This work indicated that mitochondrial ATP production and membrane potential in the dP32 mutant resembled wild-type, whereas the mutant exhibited a TS increase in both resting and evoked presynaptic calcium concentration. Taken together, the preceding findings reveal a role for dP32 in synaptic transmission and mitochondrial regulation of presynaptic calcium (Lutas, 2012).

Mitochondrial localization of P32 proteins involves an N-terminal targeting domain that is cleaved from the mature targeted protein (Honoré, 1993). Comparison of Drosophila and vertebrate P32 sequences indicates conservation of the proteolytic cleavage site in dP32. In the present study, an equivalent targeting function for the N-terminal domain of dP32 was demonstrated through its ability to mediate mitochondrial targeting. When the first 71 amino acids of dP32, including the proteolytic cleavage site, was fused to GCaMP3, this fusion protein (mito-GCaMP3) was efficiently targeted to mitochondria. Although only modest sequence conservation was observed between the N-terminal domains of dP32 and vertebrate P32 proteins, previous studies suggest that mitochondrial targeting domains vary in amino acid sequence but often share an amphipathic helical structure (Lutas, 2012).

Structural studies have established that P32 is a homotrimer in which monomers are arranged around a central pore in a donut-like structure. In the present study, homomultimerization of dP32 subunits was demonstrated in co-immunoprecipitation experiments. The trimeric structure of P32 exhibits a highly asymmetric charge distribution that creates a concentration of negatively charged residues along one side of the donut, raising the possibility that P32 may participate in calcium binding within the mitochondrial matrix (Jiang, 1999). Notably, five residues that are spatially clustered to form a pocket on the negatively charged side of human P32, Glu-89, Leu-231, Asp-232, Glu-264, and Tyr-268, are identical in the Drosophila protein. Further genetic analysis may address the importance of these clustered residues in dP32 function at synapses (Lutas, 2012).

Several possible mechanisms of dP32 function in mitochondria and synaptic transmission were considered and investigated in this paper, most notably possible roles in supporting mitochondrial membrane potential, ATP production, and presynaptic calcium signaling. Among these, the observations favor a function for dP32 in mitochondrial mechanisms regulating presynaptic calcium. Although neurotransmitter release was reduced at restrictive temperatures in dP32^EC1, the presynaptic calcium concentration was increased both at rest and in response to synaptic stimulation. It is of interest to consider why the increase in presynaptic calcium in dP32^EC1 is TS in what appears to be a complete loss-of-function mutant. Previous studies at Drosophila larval neuromuscular synapses at elevated temperatures have observed a TS increase in resting cytosolic calcium and associated inhibition of neurotransmitter release. This calcium increase was enhanced by pharmacological inhibition of presynaptic calcium clearance mechanisms or genetic removal of presynaptic mitochondria, but it remained dependent on temperature. The present findings may reflect a similar TS process involving calcium-dependent inhibition of neurotransmitter release and dP32-dependent mitochondrial mechanisms. Efforts to further address these mechanisms were pursued by employing a calcium indicator targeted to the mitochondrial matrix, mito-GCaMP3. Although this approach was successful for imaging mitochondrial calcium transients elicited by motor axon stimulation in both WT and dP32^EC1 at 20°C, robust calcium transients could not be observed in either genotype when the temperature was increased to the restrictive temperatures of 33° or 36° (Lutas, 2012).

The preceding observations suggest that sustained elevation of presynaptic calcium in the dP32 mutant may lead to reduced neurotransmitter release. Such a calcium-dependent mechanism has been reported previously in the squid giant synapse and attributed to calcium-dependent adaptation of the neurotransmitter release apparatus. Understanding the precise mechanism by which loss of dP32 impairs neurotransmitter release will require further investigation. One interesting question is how the absence of dP32 in the mitochondrial matrix leads to increased presynaptic calcium and whether this reflects the putative calcium binding capacity of this protein. Finally, while the present study is focused on the newly discovered role for P32 in neurotransmitter release, the resulting research materials are expected to facilitate in vivo analysis of P32 function in a broad range of biological processes (Lutas, 2012).

Search PubMed for articles about Drosophila P32

Chattopadhyay, C., Hawke, D., Kobayashi, R. and Maity, S. N. (2004). Human p32, interacts with B subunit of the CCAAT-binding factor, CBF/NF-Y, and inhibits CBF-mediated transcription activation in vitro. Nucleic Acids Res 32: 3632-3641. PubMed ID: 15243141

Emelyanov, A. V., Rabbani, J., Mehta, M., Vershilova, E., Keogh, M. C., Fyodorov, D. V. (2014) Drosophila TAP/p32 is a core histone chaperone that cooperates with NAP-1, NLP, and nucleophosmin in sperm chromatin remodeling during fertilization. Genes Dev 28: 2027-2040. PubMed ID: 25228646

Emelyanov, A. V. and Fyodorov, D. V. (2016).Thioredoxin-dependent disulfide bond reduction is required for protamine eviction from sperm chromatin. Genes Dev [Epub ahead of print]. PubMed ID: 28031247

Fogal, V., Richardson, A. D., Karmali, P. P., Scheffler, I. E., Smith, J. W. and Ruoslahti, E. (2010). Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol Cell Biol 30: 1303-1318. PubMed ID: 20100866

Hammoud, S. S., Nix, D. A., Zhang, H., Purwar, J., Carrell, D. T. and Cairns, B. R. (2009). Distinctive chromatin in human sperm packages genes for embryo development. Nature 460: 473-478. PubMed ID: 19525931

Honore, B., Madsen, P., Rasmussen, H. H., Vandekerckhove, J., Celis, J. E. and Leffers, H. (1993). Cloning and expression of a cDNA covering the complete coding region of the P32 subunit of human pre-mRNA splicing factor SF2. Gene 134: 283-287. PubMed ID: 8262387

Jiang, J., Zhang, Y., Krainer, A. R. and Xu, R. M. (1999). Crystal structure of human p32, a doughnut-shaped acidic mitochondrial matrix protein. Proc Natl Acad Sci U S A 96: 3572-3577. PubMed ID: 10097078

Li, Y., Wan, O. W., Xie, W. and Chung, K. K. (2011). p32 regulates mitochondrial morphology and dynamics through parkin. Neuroscience 199: 346-358. PubMed ID: 22008525

Lutas, A., Wahlmark, C. J., Acharjee, S. and Kawasaki, F. (2012). Genetic analysis in Drosophila reveals a role for the mitochondrial protein p32 in synaptic transmission. G3 (Bethesda) 2: 59-69. PubMed ID: 22384382

Miller, D., Brinkworth, M. and Iles, D. (2010). Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction 139: 287-301. PubMed ID: 19759174

Ohrmalm, C. and Akusjarvi, G. (2006). Cellular splicing and transcription regulatory protein p32 represses adenovirus major late transcription and causes hyperphosphorylation of RNA polymerase II. J Virol 80: 5010-5020. PubMed ID: 16641292

Orsi, G. A., Algazeery, A., Meyer, R. E., Capri, M., Sapey-Triomphe, L. M., Horard, B., Gruffat, H., Couble, P., Ait-Ahmed, O. and Loppin, B. (2013). Drosophila Yemanuclein and HIRA cooperate for de novo assembly of H3.3-containing nucleosomes in the male pronucleus. PLoS Genet 9: e1003285. PubMed ID: 23408912

Petersen-Mahrt, S. K., Estmer, C., Ohrmalm, C., Matthews, D. A., Russell, W. C. and Akusjarvi, G. (1999). The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation. EMBO J 18: 1014-1024. PubMed ID: 10022843

Rathke, C., Baarends, W. M., Awe, S. and Renkawitz-Pohl, R. (2014). Chromatin dynamics during spermiogenesis. Biochim Biophys Acta 1839: 155-168. PubMed ID: 24091090

Wang, J. T., Xu, X., Alontaga, A. Y., Chen, Y. and Liu, Y. (2014). Impaired p32 regulation caused by the lymphoma-prone RECQ4 mutation drives mitochondrial dysfunction. Cell Rep 7: 848-858. PubMed ID: 24746816

Wu, H., Sun, H., Liang, X., Lima, W. F. and Crooke, S. T. (2013). Human RNase H1 is associated with protein P32 and is involved in mitochondrial pre-rRNA processing. PLoS One 8: e71006. PubMed ID: 23990920

Xiao, K., Wang, Y., Chang, Z., Lao, Y. and Chang, D. C. (2014). p32, a novel binding partner of Mcl-1, positively regulates mitochondrial Ca(2+) uptake and apoptosis. Biochem Biophys Res Commun 451: 322-328. PubMed ID: 25091479

Yagi, M., Uchiumi, T., Takazaki, S., Okuno, B., Nomura, M., Yoshida, S., Kanki, T. and Kang, D. (2012). p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding ability. Nucleic Acids Res 40: 9717-9737. PubMed ID: 22904065

Zheng, Y. H., Yu, H. F. and Peterlin, B. M. (2003). Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nat Cell Biol 5: 611-618. PubMed ID: 12833064

date revised: 29 September 2014

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