What is SIN3A?
SIN3A (SIN3 transcription regulator family member A) is a transcriptional regulatory protein with paired amphipathic helix (PAH) domains that support protein-protein interactions and may mediate repression by the Mad-Max complex. The SIN3A protein acts as a scaffold within multi-protein complexes to silence gene expression via histone deacetylation. Pathogenic variants or deletions of the SIN3A gene are associated with Witteveen-Kolk syndrome (WITKOS), a neurodevelopmental disorder characterized by short stature, microcephaly, and mild intellectual or developmental delay.
Because the SIN3A gene is important for brain activity, many people who have SIN3A-related syndrome can have mild intellectual disability or developmental delays, motor delays, a small head, short height, hyperactivity, limb defects, congenital disabilities, defects in the heart, eye, or intestinal tract, behavioral issues, and sometimes seizures.
The Mad-Max complex is a nuclear protein complex that acts as a sequence-specific transcriptional repressor, a heterodimer formed by a Mad family protein (such as MAD1/MXD1) binding to its obligate partner MAX (MYC-associated factor X) that competes directly with the oncogenic Myc:Max heterodimer for the same DNA binding sites (E-box sequences). While Myc:Max activates cell growth and proliferation, the Mad:Max complex does the opposite: it suppresses gene transcription, halts cell-cycle progression (S-phase), and promotes cellular differentiation, such as the transition of monocytes into macrophages.
The Mad-Max complex recruits corepressors including mSin3 and histone deacetylases (HDACs) to condense chromatin and silence target genes, functioning as a candidate tumor suppressor. Mammalian Sin3 proteins interact with the Mad components of the Myc/Max/Mad network of cell growth regulators. Mad/Max complexes may recruit mammalian Rpd3-like enzymes, thereby directing histone deacetylase activity to promoters and negatively regulating cell growth.
According to Brubaker et al. (2000), Sin3 appears to function as a large protein scaffold capable of multiple protein–protein interactions. On the one hand, Sin3 interacts with class I histone deacetylases (HDAC1 and HDAC2) and presumed accessory proteins such as RbAp48, SAP30, and SAP18. In contrast, Sin3 associates with a wide range of DNA-binding transcription factors, including nuclear hormone receptors (through the N-CoR and SMRT corepressors), MeCP2, Ski, p53, Ikaros and Aiolos, REST/NRSF, MNF-β, and the Mad family of Max-binding bHLH-Zip transcriptional repressors. The activities of these proteins and their ability to interact with Sin3 are thought to be crucial for cell proliferation and differentiation.
| Solution structure of Sds3 in complex with Sin3A. [2N2H] | NMR STRUCTURE OF THE HUMAN MAD1 TRANSREPRESSION DOMAIN SID IN COMPLEX WITH MAMMALIAN SIN3A PAH2 DOMAIN [1G1E] |
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>pdb|2N2H|A Chain A, Sin3 histone deacetylase corepressor complex component SDS3 SNAAQLNYLL TDEQIMEDLR TLNKLKS >pdb|2N2H|B Chain B, Paired amphipathic helix protein Sin3a SNAEHIYRCE DERFELDVVL ETNLATIRVL EAIQKKLSRL SAEEQAKFRL DNTLGGTSEV IHRKALQRIY ADKAADIIDG LRKNPSIAVPIVLKRLKMKE EEWREAQRGF NKVWREQNEK YYLKS The sequence regions that interphase in the complex are highlighted in black. | >pdb|1G1E|A Chain A, MAD1 PROTEIN RMNIQMLLEAADYLER >pdb|1G1E|B Chain B, SIN3A SLQNNQPVEF NHAINYVNKI KNRFQGQPDI YKAFLEILHT YQKEQRNAKE AGGNYTPALT EQEVYAQVAR LFKNQEDLLS EFGQFLPDA Binding Motif 1PD7 Mad1 VRMNIQMLLEAADYLERREREAEH 1G1E MAD1 RMNIQMLLEAADYLER 2N2H sIN3 SNAAQLNYLLTDEQIMEDLRTLNKLKS |
Highlights from Bansal et al. (2015) and Kadamb et al. (2021)
The SIN3 molecular scaffold and its paired amphipathic α-helix (PAH2) domain interact with the plant homeodomain (PHD)-containing adaptor protein PF1 (PHF12), which links to chromatin-modifying complexes containing MRG15 and KDM5A/B.
The PAH2 domain of SIN3A is a therapeutic target; when it is prevented from binding PF1, it inhibits the invasive phenotype in triple-negative breast cancer (TNBC).
Epigenetic repression of integrin expression and downstream pathways results from enhanced binding of KLF9 /SIN3A repressor complex to their promoters.
Genome-wide transcriptomic analysis showed downregulation of multiple invasion-related genes. Tumor growth and lung metastasis were markedly decreased in vivo.
Kadamb et al.'s studies suggest that PF1 may act as a gatekeeper for trafficking SID protein binding to PAH2 of SIN3A and plays a functional role in the presentation of different regulatory complexes.
Blocking PAH2 function offers a promising targeted therapy approach to inhibit the invasive phenotype in TNBC.
References
Bansal N, Petrie K, Christova R, Chung CY, Leibovitch BA, Howell L, Gil V, Sbirkov Y, Lee E, Wexler J, Ariztia EV, Sharma R, Zhu J, Bernstein E, Zhou MM, Zelent A, Farias E, Waxman S. Targeting the SIN3A-PF1 interaction inhibits epithelial to mesenchymal transition and maintenance of a stem cell phenotype in triple negative breast cancer. Oncotarget. 2015 Oct 27;6(33):34087-105. [PMC]
Brubaker K, Cowley SM, Huang K, Loo L, Yochum GS, Ayer DE, Eisenman RN, Radhakrishnan I. Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex. Cell. 2000 Nov 10;103(4):655-65. [Cell] 1G1E: NMR STRUCTURE OF THE HUMAN MAD1 TRANSREPRESSION DOMAIN SID IN COMPLEX WITH MAMMALIAN SIN3A PAH2 DOMAIN
Clark MD, Marcum R, Graveline R, Chan CW, Xie T, Chen Z, Ding Y, Zhang Y, Mondragón A, David G, Radhakrishnan I. Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):E3669-78. [PMC] 2N2H: Solution structure of Sds3 in complex with Sin3A.
Kadamb R, Leibovitch BA, Farias EF, Dahiya N, Suryawanshi H, Bansal N, Waxman S. Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A-PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1. Transl Oncol. 2022 Feb;16:101320. [PMC]