The BIRC6 gene comprises 75 exons resulting in a transcript of 16066 bps. The ATG is in the first exon.

Only one variant of BIRC6 has been found so far which comprises 14490 bps. There are several synonymous and nonsynonymous SNPs reported for BIRC6 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R).

Not known. There is evidence for a processed pseudogene in M. musculus.

BIRC6 contains two functionally validated domains: A N-terminal BIR repeat (SMART SM00238, aa: 256-332) and a C-terminal UBC domain (SMART SM00212, aa: 4548 - 4712). The BIR repeat is needed for interactions with caspases and IAP-binding motif (IBM) containing proteins (HtrA2, Smac). The UBC domain can form a thiolester linkage with ubiquitin transferred by E1.
Between aa 1589-1633 a coiled-coil region can be found.

BIRC6 is highly expressed in brain, testis, lymphatic cells and secretory organs and also found in any other tissues (Hauser et al., 1998). It is highly expressed in the mouse embryos up to E11 and then transcript levels drop. Single-cell RNA cytometry analysis revealed a bi-modal distributed Birc6 mRNA expression heterogeneity within mouse hematopoietic stem cell (HSC) population. Upon ageing, BIRC6-high expressing HSC cells were shown to out-compete Birc6-low cells (Dimov et al., 2014). BIRC6 is frequently elevated in various cancer tissues.

Localized to membranes of the trans Golgi network (TGN) and the endosomal system (Hauser et al., 1998). BIRC6 relocalizes considerably during the cell cycle. It concentrates in a pericentriolar compartment in interphase, moves partially to spindle poles in metaphase, and finally localizes to the spindle midzone and the midbody in telophase and during cytokinesis (Pohl and Jentsch, 2008).

Inhibitor of apoptosis. BIRC6 is a peripheral membrane protein of the trans-Golgi network that protects cells from apoptosis by functioning as an inhibitor of apoptosis protein (IAP). BIRC6 can bind and inhibit activated caspases CASP-3, CASP-6, CASP-7, CASP-8 and CASP-9. Furthermore it ubiquitylates caspase-9, HtrA2 (a pro-apoptotic serine protease) and DIABLO/Smac (a competitor for caspase-IAP interactions) thereby targeting them for proteasomal degradation. The ubiquityltion reactions do not require an ubiquitin E3 ligase making BIRC6 a chimeric E2/E3 ubiquitin ligase (Bartke et al., 2004; Hao et al., 2004). More importantly, distinct from other IAP members, BIRC6 is able to antagonize both precursor and mature forms of Smac and caspase-9. The ability to antagonize precursor apoptotic molecules represents an important mechanism for the prevention of apoptosis under normal conditions (Qiu and Goldberg, 2005). On the other hand, BIRC6 also inhibits apoptosis via negatively regulating p53 protein levels by facilitating its degradation via ubiquitination (Ren et al., 2005; Tang et al., 2014).
BIRC6 and treatment resistance. Silencing of BIRC6 has been shown to sensitize cancer cells to various anticancer agents, including 5-fluorouracil (in cervical, fibrosarcoma and breast cancer cells) (Chu et al., 2008), oxaliplatin and cisplatin (in colonospheres) (Van Houdt et al., 2011), MEK inhibitor, BRAFV600E-specific inhibitor and soluble or membrane-bound TRAIL (in melanoma cells) (Tassi et al., 2012), cisplatin (in non-small cell lung cancer and glioma) (Dong et al., 2013; Chen et al., 1999), camptothecin (glioma) (Chen et al., 1999) and sorafenib (in hepatoma) (Tang et al., 2014).
Essential in embryonic development. Targeted disruption of BIRC6 in mice caused embryonic and neonatal lethality. BIRC6 homozygous-mutant embryos which did not express BIRC6 all died immediately after birth. At E18.5, viable mutant embryos had normal appearance, but were significantly smaller (10-20% less body weight) than control littermates. Macroscopic analysis of mutant embryos at E15.5 revealed that more than half of them had severely defective angiogenesis that often coincided with severe oedema (Hao et al., 2004). Consistantly, BIRC6 knock-out mice showed retarded growth and poor vascularization from E13.5 and perinatal lethality (Lotz et al., 2004). BIRC6 mutant mice were embryonic lethal (Hitz et al., 2000; Ren et al., 2005).
Regulator of cytokinesis. BIRC6 is a major regulator of abscission, the final stage of cytokinesis. During cytokinesis, BIRC6 moves from the vesicular system to the midbody ring and serves as a platform for the membrane delivery machinery and mitotic regulators. Depletion of BIRC6 in cell cultures causes defective abscission and cytokinesis-associated apoptosis, accompanied by a block of vesicular targeting and defective formation of the midbody and the midbody ring. BIRC6 coordinates multiple steps required for abscission including the relocalization of ubiquitin from midbody microtubules to the midbody ring during cytokinesis (Pohl and Jentsch, 2008).
Novel regulator of mitosis. BIRC6 interacts with cyclin A and promotes its degradation in early mitosis. BIRC6 also interacts with APC/C, and it facilitates cyclin A ubiquitylation. The elimination of cyclin A and cyclin B are essential for entry into mitosis. BIRC6 -deficient MEF cells exhibit earlier replicative senescence, large nuclei with excess centrosome, and mitotic delay. BIRC6 facilitates the ubiquitylation of CYCLIN A by recruiting it to APC/C without the need of a functional UBC domain, suggesting its role as a substrate recognition subunit in a complex of ubiquitin ligase (Kikuchi et al., 2014).
BIRC6 and autophagy. Functional BIRC6 is required to inhibit autophagy under nutrient-rich conditions in D. melanogaster oogenesis. Lack of BIRC6 function in BIR-domain deleted flies resulted in an increase in both autophagic punctate and TUNEL staining in germaria and degenerating midstage egg chambers (Hou et al., 2008). On the contrary, recent evidence suggested that BIRC6 may promote autophagy in prostate cancer cells. Silencing of BIRC6 was showed to decrease Beclin-1 protein, LC3 cleavage and reduce LC3 punctate formation (Low et al., 2013).

Regulation of BIRC6
Despite the ability of BIRC6 to target caspases, Smac and HtrA2, BIRC6 is also negatively regulated by these pro-apoptotic molecules. Caspase-3 and HtrA2 are capable of cleaving BIRC6 and inhibit its anti-apoptotic function. Smac inhibits the IAP function of BIRC6 by its ability to block BIRC6-caspase binding (Bartke et al., 2004; Sekine et al., 2005). Nrdp1, a RING finger containing ubiquitin ligase, promotes proteasomal degradation of BIRC6 (Qiu et al., 2004).
Epstein-Barr Virus (EBV) microRNAs (miRNAs) processed from the BHRF1 and BamHI A rightward (BART) transcript, miR-BART15-3p, targets the 3 untranslated region (UTR) of BIRC6. miR-BART15-3p inhibits the translation of BIRC6 protein in EBV-infected gastric carcinoma cells and contributes to host cells apoptosis induction (Choi et al., 2013). In muscle, prostaglandin F2a upregulates BIRC6 which promotes muscle cell survival and growth (Jansen and Pavlath, 2008).

- ubc-17 (C. elegans)
- IAP6 (A. gambiae)
- Bruce (D. melanogaster)
- BIRC6 (X. tropicalis)
- Birc6 (M. musculus)

There are several synonymous and nonsynonymous SNPs reported for BIRC6 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R).