Sin3A 結合蛋白 130 (Sin3A associated protein 130, SAP130)最初被發現與 mSin3A 輔抑制複合物的結合蛋白之一。 mSin3A 輔抑制複合物含有 7 至 10 個 次單元（例如:SAP25、SAP45、SAP30、SAP30L 和 SAP180/ARID4B），並且通 過組蛋白去乙醯化在轉錄調控中扮演重要的角色。 Sin3A 輔抑制複合物調節各 種基因表達並參與各種細胞生理。此外，Sin3A 輔抑制複合物是迄今為止特徵最 為罕見的哺乳動物共抑制複合物之一。文獻已報導 Sin3A 與 N-CoR 和 SMRT (silencing mediator of retinoid and thyroid hormone receptor)轉錄輔抑制物相互作 用，並作為甲狀腺素和類視黃醇激素受體的沉默介質。值得注意的是，SUMO 修飾（SUMOylation）已被聯繫到賦予幾個轉錄因子和輔因子的抑制性質。最近， 我們注意到 SAP130 的 C-端含有三個保守的[IVL] KxE SUMO-結合基序，我們 假設 SAP130 可能是 SUMO1 共軛鍵結目標。使用體內和體外 SUMO 鍵結反應 試驗，我已經證明 SAP130 可以通過 SUMO1 共軛鍵結進行修飾。我進一步創建 了 SAP130 的三個離胺酸-丙胺酸突變體，並且證明 SAP130-KA 突變體沒有顯示 任何 SUMO1 共軛鍵結結合。我的研究還顯示 SAP130 SUMOylation 有助於 SAP130 對鹽皮質激素受體（Mineralocorticoid receptor, MR）的轉錄抑制作用。 未來需要進一步研究闡明 SUMOylation SAP130 在其他核激素受體所參與的轉 錄和生物學功能中的作用。

The Sin3A-associated protein 130 (SAP130) was initially identified as one of protein associated with the mSin3A corepressor complex. The mSin3A corepressor complex contains 7 to 10 associated subunits (i.e., SAP25, SAP45, SAP30, SAP30L, and SAP180/ARID4B) and play an important role in transcriptional regulation through histone deacetylation. The Sin3A complex regulates a wide variety of genes expression and that participate in various cellular events. In addition, the Sin3A complex is among the very rare mammalian transcriptional corepressor complexes that have been characterized up to the present. Sin3A have been reported to interact with N-CoR and SMRT transcriptional corepressors and function as silencing mediators for thyroid and retinoid hormone receptors. Notably, SUMO modification (SUMOylation) has been linked to impart repressive properties on several transcription factors and cofactors. Recently, we noticed that the C-terminal domain of SAP130 contains three conserved [I/V/L]KxE SUMO-conjugation motifs. We hypothesized that SAP130 might be a target for SUMO1 conjugation. Using in vivo and in vitro SUMOylation assays, I have demonstrated that SAP130 could be modified by SUMO1 conjugation. I further created the three lysine-to-alanine mutant of SAP130, and the SAP130-KA mutant did not show any SUMO1 conjugation. My study also revealed that the SAP130 SUMOylation is contributed to the transcriptional repressive effects of SAP130 on mineralocorticoid receptor (MR). Further investigation is required to elucidate the role of SUMOylated SAP130 in other nuclear hormone receptors-mediated transcription and biological functions.

1. Seeler, J.S. and A. Dejean, SUMO and the robustness of cancer, in Nat Rev
Cancer. 2017. p. 184-197.
2. Carter, S., et al., C-terminal modifications regulate MDM2 dissociation and
nuclear export of p53. Nat Cell Biol, 2007. 9(4): p. 428-35.
3. Huang, J., et al., SUMO1 modification of PTEN regulates tumorigenesis by
controlling its association with the plasma membrane. Nat Commun, 2012. 3: p.
911.
4. Lallemand-Breitenbach, V., et al., Arsenic degrades PML or PML-RARalpha
through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol,
2008. 10(5): p. 547-55.
5. Tatham, M.H., et al., RNF4 is a poly-SUMO-specific E3 ubiquitin ligase
required for arsenic-induced PML degradation. Nat Cell Biol, 2008. 10(5): p.
538-46.
6. Tirard, M., et al., Sumoylation and proteasomal activity determine the
transactivation properties of the mineralocorticoid receptor. Mol Cell
Endocrinol, 2007. 268(1-2): p. 20-9.
7. Fleischer, T.C., U.J. Yun, and D.E. Ayer, Identification and characterization of
three new components of the mSin3A corepressor complex. Mol Cell Biol,
2003. 23(10): p. 3456-67.
8. Hoege, C., et al., RAD6-dependent DNA repair is linked to modification of
PCNA by ubiquitin and SUMO. Nature, 2002. 419(6903): p. 135-41.
9. Pfander, B., et al., SUMO-modified PCNA recruits Srs2 to prevent
recombination during S phase. Nature, 2005. 436(7049): p. 428-33.
10. Guo, B., et al., Signalling pathways and the regulation of SUMO modification.
Biochem Soc Trans, 2007. 35(Pt 6): p. 1414-8.
11. Geoffroy, M.C. and R.T. Hay, An additional role for SUMO in
ubiquitin-mediated proteolysis. Nat Rev Mol Cell Biol, 2009. 10(8): p. 564-8.
12. Cubenas-Potts, C. and M.J. Matunis, SUMO: a multifaceted modifier of
chromatin structure and function. Dev Cell, 2013. 24(1): p. 1-12.
13. Droescher, M., V.K. Chaugule, and A. Pichler, SUMO rules: regulatory
concepts and their implication in neurologic functions. Neuromolecular Med,
2013. 15(4): p. 639-60.
14. Flotho, A. and F. Melchior, Sumoylation: a regulatory protein modification in
health and disease. Annu Rev Biochem, 2013. 82: p. 357-85.
15. Mattoscio, D., C.V. Segre, and S. Chiocca, Viral manipulation of cellular
protein conjugation pathways: The SUMO lesson. World J Virol, 2013. 2(2): p.
79-90.
16. Chymkowitch, P., P.A. Nguea, and J.M. Enserink, SUMO-regulated
transcription: challenging the dogma. Bioessays, 2015. 37(10): p. 1095-105.
17. Eifler, K. and A.C.O. Vertegaal, SUMOylation-Mediated Regulation of Cell
Cycle Progression and Cancer. Trends Biochem Sci, 2015. 40(12): p. 779-793.
18. Garcia-Rodriguez, N., R.P. Wong, and H.D. Ulrich, Functions of Ubiquitin and
SUMO in DNA Replication and Replication Stress. Front Genet, 2016. 7: p.
87.
19. Nie, M. and M.N. Boddy, Cooperativity of the SUMO and Ubiquitin Pathways
in Genome Stability. Biomolecules, 2016. 6(1): p. 14.
20. Hendriks, I.A. and A.C. Vertegaal, A comprehensive compilation of SUMO
proteomics. Nat Rev Mol Cell Biol, 2016. 17(9): p. 581-95.
21. Shen, T.H., et al., The mechanisms of PML-nuclear body formation. Mol Cell,
2006. 24(3): p. 331-9.
22. Smith, C.L., et al., A separable domain of the p150 subunit of human chromatin
assembly factor-1 promotes protein and chromosome associations with nucleoli.
Mol Biol Cell, 2014. 25(18): p. 2866-81.
23. Chu, K., X. Niu, and L.T. Williams, A Fas-associated protein factor, FAF1,
potentiates Fas-mediated apoptosis. Proc Natl Acad Sci U S A, 1995. 92(25): p.
11894-8.
24. Ryu, S.W., et al., Fas-associated factor 1, FAF1, is a member of Fas
death-inducing signaling complex. J Biol Chem, 2003. 278(26): p. 24003-10.
25. Park, M.Y., et al., Fas-associated factor-1 inhibits nuclear factor-kappaB
(NF-kappaB) activity by interfering with nuclear translocation of the RelA (p65)
subunit of NF-kappaB. J Biol Chem, 2004. 279(4): p. 2544-9.
26. Park, M.Y., et al., FAF1 suppresses IkappaB kinase (IKK) activation by
disrupting the IKK complex assembly. J Biol Chem, 2007. 282(38): p.
27572-7.
27. Song, E.J., et al., Human Fas-associated factor 1, interacting with ubiquitinated
proteins and valosin-containing protein, is involved in the
ubiquitin-proteasome pathway. Mol Cell Biol, 2005. 25(6): p. 2511-24.
28. Obradovic, D., et al., DAXX, FLASH, and FAF-1 modulate mineralocorticoid
and glucocorticoid receptor-mediated transcription in hippocampal
cells--toward a basis for the opposite actions elicited by two nuclear receptors?
Mol Pharmacol, 2004. 65(3): p. 761-9.
29. Nagy, L., et al., Nuclear receptor repression mediated by a complex containing
SMRT, mSin3A, and histone deacetylase. Cell, 1997. 89(3): p. 373-80.
30. Shinbo, Y., et al., Proper SUMO-1 conjugation is essential to DJ-1 to exert its
full activities. Cell Death Differ, 2006. 13(1): p. 96-108.
31. Lallemand-Breitenbach, V., et al., Role of promyelocytic leukemia (PML)
sumolation in nuclear body formation, 11S proteasome recruitment, and
As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp
Med, 2001. 193(12): p. 1361-71.
32. Rabellino, A., et al., The SUMO E3-ligase PIAS1 regulates the tumor
suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res, 2012.
72(9): p. 2275-84.
33. Zhang, L., et al., Fas-associated factor 1 antagonizes Wnt signaling by
promoting beta-catenin degradation. Mol Biol Cell, 2011. 22(9): p. 1617-24.
34. Zhang, L., et al., Fas-associated factor 1 is a scaffold protein that promotes
beta-transducin repeat-containing protein (beta-TrCP)-mediated beta-catenin
ubiquitination and degradation. J Biol Chem, 2012. 287(36): p. 30701-10.
35. Ji, Q., et al., CRL4B interacts with and coordinates the SIN3A-HDAC complex
to repress CDKN1A and drive cell cycle progression. J Cell Sci, 2014. 127(Pt
21): p. 4679-91.
36. Underhill, C., et al., A novel nuclear receptor corepressor complex, N-CoR,
contains components of the mammalian SWI/SNF complex and the corepressor
KAP-1. J Biol Chem, 2000. 275(51): p. 40463-70.
37. Jepsen, K. and M.G. Rosenfeld, Biological roles and mechanistic actions of
co-repressor complexes. J Cell Sci, 2002. 115(Pt 4): p. 689-98.
38. McDonel, P., I. Costello, and B. Hendrich, Keeping things quiet: roles of
NuRD and Sin3 co-repressor complexes during mammalian development. Int J
Biochem Cell Biol, 2009. 41(1): p. 108-16.
39. Heideman, M.R., et al., Sin3a-associated Hdac1 and Hdac2 are essential for
hematopoietic stem cell homeostasis and contribute differentially to
hematopoiesis. Haematologica, 2014. 99(8): p. 1292-303.
40. Yang, W. and W. Paschen, SUMO proteomics to decipher the SUMO-modified
proteome regulated by various diseases. Proteomics, 2015. 15(5-6): p. 1181-91.
41. Laitaoja, M., et al., Redox-dependent disulfide bond formation in SAP30L
corepressor protein: Implications for structure and function. Protein Sci, 2016.
25(3): p. 572-86.