However, its specific function in the HIRA complex remains to be determined. CABIN1, originally identified as a Calcineurin-binding protein whose interaction is dependent on protein kinase C (pKC) and calcium signals, negatively regulates the activity of other interactors, such as Myocyte enhancer factor 2 (MEF2) and p53 16, 17, 18. However, whether UBN1 and UBN2 are present together in the same complex or constitute distinct entities is not known. Notably, in addition to UBN1, another Ubinuclein exists, UBN2, that is also able to interact with HIRA 15. Within the HIRA complex, a Hpc2-related domain (HRD) of UBN1 interacts directly with H3.3 as revealed by in vitro biochemical studies and X-ray crystallography 14. Moreover, it has been involved in either the activation or the long-term maintenance of gene expression patterns 11, 12 and HIRA depletion has been reported to affect transcription recovery after DNA repair 13. The HIRA-mediated H3.3 deposition has been strongly associated with actively transcribed genes 10. ASF1a interacts specifically with the HIRA subunit connecting this chaperone with the DNA synthesis-independent assembly pathway mediated by the HIRA complex 8, 9. In addition to the HIRA complex, other histone chaperones, in particular Anti-silencing factor 1 (ASF1a and ASF1b), have been purified with H3.3 3. Notably, these three components have counterparts in yeast that constitute the HIR complex 7. HIRA is in a complex that contains at least two other subunits, Calcineurin-binding protein 1 (CABIN1) and Ubinuclein 1 (UBN1) 6. HIRA promotes histone deposition independently of DNA synthesis as shown in Xenopus laevis egg extracts 4 and deposits new histones H3.3 in both replicating and non-replicating human cells 5. The presence of the Histone regulator A (HIRA) with the histone variant H3.3 in a soluble complex has implicated this histone chaperone in the specific deposition of this variant 3. Histone chaperones are currently considered the most likely candidates responsible for histone variant deposition 1, 2.

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