PAX5 (paired box gene 5)

9p13.2

391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304-359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011).

NCOR1 (nuclear receptor corepressor 1)

17p12

2440 amino acids; from N-term to C-term, NCOR1 contains: a repression domains (responsible for the repressive activity of the corepressor) (aa 1-312); a poly-Gln stretch (aa 58-64), two coiled coil domains (aa 174-216 and aa 299-328); a SANT (Swi3, Ada2, NCoR1, TFIIB) domain (deacetylase activation domain (DAD)) (aa 435-486); a coiled coil domain (aa 501-557); a poly-Ala stretch (aa 593-603); a Pro-rich stretch (aa 607-617); a SANT domain (histone interaction domain (HID)) (aa 623-674); a poly-Pro stretch (aa 1032-1035); a poly-Ala stretch (aa 1707-1712); a CoRNR box motif (Leu-x-x-Leu-Leu motifs) (aa 1933-1937); a poly-Ser stretch (aa 1952-1963); a nuclear receptor-interacting domain ID1 (aa 2032-2115); a CoRNR box motif (aa 2055-2059); another nuclear receptor-interacting domain ID2 (aa 2212-2273); and a CoRNR box motif (aa 2263-2267).

NCOR1 and NCOR2 (12q24, also called SMRT) are transcriptional corepressors that associate with nuclear hormone receptors (thyroid hormone receptors and retinoic acid receptors) in the absence of ligand. Thyroid hormone receptors interact specifically with the ID3 and ID2 domains of NCOR1 (ID domains contain an isoleucine-rich domain, named the CoRNR box, this CoRNR box is required for nuclear hormone receptors interaction). SANT-like domains promote histone deacetylation. Repression is mediated by formation of a large corepressor complex that contains SIN3A/B (15q24 and 19p13), recruiting multiple histone deacetylase enzymes such as HDAC1 (1p35), HDAC2 (6q21), HDAC3 (5q31), HDAC4 (2q37), HDAC7 (12q13), and SIRT1 (10q21), resulting in the formation of repressive chromatin structures. This complex associates with the thyroid hormone receptor and the retinoic acid receptor.

NCOR1 and NCOR2 also interact with many other transcription factors including: BCL6 (3q27), RUNX1T1 (8q21, also called ETO), SPEN (1p36, also called SHARP), ZBTB33 (Xq24), HEXIM1 (17q21), TBL1XR1 (3q26), MEF2C (5q14), CNOT2 (12q15), and RBJP (4p15), Jun proteins and the NFKB pathway (Li et al., 1997; Watson et al., 2012; Mottis et al., 2013).