HGNC Approved Gene Symbol: ENDOG
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:128,818,500-128,822,676 (from NCBI)
Tiranti et al. (1995) mapped 3 human housekeeping genes involved in mitochondrial biogenesis. One of these was the gene encoding a mitochondrion-specific endonuclease, designated ENDOG, that preferentially cleaves DNA stretches rich in C and G residues. The authors hypothesized that this endonuclease could play a role in the maturation of RNA complementary stretches serving as primers for mtDNA replication, in the splicing process of polycistronic transcripts, or in mtDNA repair.
Li et al. (2001) identified endoG as the nuclease specifically activated by apoptotic stimuli and able to induce nucleosomal fragmentation of DNA in fibroblast cells from embryonic mice lacking DFF45 (601882). EndoG is a mitochondrion-specific nuclease that translocates to the nucleus during apoptosis. Once released from mitochondria, endoG cleaves chromatin DNA into nucleosomal fragments independently of caspases (see 147678). Therefore, ENDOG represents a caspase-independent apoptotic pathway initiated from the mitochondria.
In C. elegans, Parrish et al. (2001) found that reduction of activity of cps6, a homolog of ENDOG, affected normal DNA degradation and resulted in delayed appearance of cell corpses during development. This observation provided in vivo evidence that the DNA degradation process is important for proper progression of apoptosis. Parrish et al. (2001) stated that CPS6 is the first mitochondrial protein identified to be involved in programmed cell death in C. elegans, underscoring the conserved and important role of mitochondria in the execution of apoptosis.
Genomic inversion occurs during herpes simplex virus-1 DNA replication. Using RNA interference, Huang et al. (2006) showed that reduced ENDOG levels produced a small but statistically significant decrease in this process. They also observed that reduced ENDOG levels resulted in a deficiency in cell proliferation, and cells appeared to be arrested in the G2 phase of the cell cycle.
McDermott-Roe et al. (2011) applied integrative genomics to dissect a highly replicated, blood pressure-independent left ventricular mass locus on rat chromosome 3p and identified Endog, which had been implicated in apoptosis but not hypertrophy, as the gene at the locus. McDermott-Roe et al. (2011) found a loss-of-function mutation in Endog that was associated with increased left ventricular mass and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of prohypertrophic stimulation. Genomewide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. McDermott-Roe et al. (2011) showed direct regulation of ENDOG by ERR-alpha (601998) and PGC1-alpha (604517), which are master regulators of mitochondrial and cardiac function, as well as interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction, and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. McDermott-Roe et al. (2011) concluded that their study further established the link between mitochondrial dysfunction, reactive oxygen species, and heart disease and uncovered a role for Endog in maladaptive cardiac hypertrophy.
By PCR-based screening of a somatic cell hybrid panel and by fluorescence in situ hybridization, Tiranti et al. (1995) assigned the ENDOG locus to 9q34.1.
Zhang et al. (2003) found that EndoG -/- mouse embryos died between embryonic days 2.5 and 3.5. Mitochondrial DNA copy numbers in ovulated oocytes from EndoG heterozygous mutant and wildtype mice were similar, suggesting that EndoG is involved in a cellular function unrelated to mitochondrial DNA replication. Cells from heterozygous mutant mice exhibited increased resistance to TNFA (191160)- and saurosporine-induced cell death. Moreover, spontaneous cell death of spermatogonia in EndoG heterozygous mutant mice was significantly reduced. DNA fragmentation was also reduced in EndoG +/- thymocytes and splenocytes, as well as in thymus in vivo, compared with wildtype cells, upon activation of apoptosis.
Huang, K.-J., Ku, C.-C., Lehman, I. R. Endonuclease G: a role for the enzyme in recombination and cellular proliferation. Proc. Nat. Acad. Sci. 103: 8995-9000, 2006. [PubMed: 16754849] [Full Text: https://doi.org/10.1073/pnas.0603445103]
Li, L. Y., Luo, X., Wang, X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412: 95-99, 2001. [PubMed: 11452314] [Full Text: https://doi.org/10.1038/35083620]
McDermott-Roe, C., Ye, J., Ahmed, R., Sun, X.-M., Serafin, A., Ware, J., Bottolo, L., Muckett, P., Canas, X., Zhang, J., Rowe, G. C., Buchan, R., and 23 others. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function. Nature 478: 114-118, 2011. [PubMed: 21979051] [Full Text: https://doi.org/10.1038/nature10490]
Parrish, J., Li, L., Klotz, K., Ledwich, D., Wang, X., Xue, D. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 412: 90-94, 2001. [PubMed: 11452313] [Full Text: https://doi.org/10.1038/35083608]
Tiranti, V., Rossi, E., Ruiz-Carrillo, A., Rossi, G., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis. Genomics 25: 559-564, 1995. [PubMed: 7789991] [Full Text: https://doi.org/10.1016/0888-7543(95)80058-t]
Zhang, J., Dong, M., Li, L., Fan, Y., Pathre, P., Dong, J., Lou, D., Wells, J. M., Olivares-Villagomez, D., Van Kaer, L., Wang, X., Xu, M. Endonuclease G is required for early embryogenesis and normal apoptosis in mice. Proc. Nat. Acad. Sci. 100: 15782-15787, 2003. [PubMed: 14663139] [Full Text: https://doi.org/10.1073/pnas.2636393100]