7yho

Structural highlights

Disease

SRY_HUMAN Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:400044. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients manifest rapid and early degeneration of their gonads, which are present in the adult as 'streak gonads', consisting mainly of fibrous tissue and variable amounts of ovarian stroma. As a result these patients do not develop secondary sexual characteristics at puberty. The external genitalia in these subjects are completely female, and Muellerian structures are normal.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]} [:]^{[14] [15] [16] [17]} [:]^{[18] [19] [20] [21] [22] [23]} Note=A 45,X chromosomal aberration involving SRY is found in Turner syndrome, a disease characterized by gonadal dysgenesis with short stature, "streak gonads", variable abnormalities such as webbing of the neck, cubitus valgus, cardiac defects, low posterior hair line. The phenotype is female. Defects in SRY are the cause of 46,XX sex reversal type 1 (SRXX1) [MIM:400045. A condition in which male gonads develop in a genetic female (female to male sex reversal).^{[24] [25]}

Function

SRY_HUMAN Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (By similarity). In male adult brain involved in the maintenance of motor functions of dopaminergic neurons (By similarity). Involved in different aspects of gene regulation including promoter activation or repression (By similarity). Promotes DNA bending. SRY HMG box recognizes DNA by partial intercalation in the minor groove. Also involved in pre-mRNA splicing. Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3'.^{[26] [27] [28] [29]} ROS1_ARATH Bifunctional DNA glycosylase/lyase, which excises 5-methylcytosine (5-meC) and 5-hydroxymethylcytosine (5-hmeC), leaving an apyrimidinic (AP) site that is subsequently incised by the lyase activity (PubMed:25240767). Generates 3'-phosphor-alpha,beta-unsaturated aldehyde (3'-PUA) as a primary 5-meC excision intermediate (PubMed:25228464). Prevents DNA hypermethylation, specifically in the promoter of otherwise silenced loci. May be involved in DNA repair through its nicking activity on methylated DNA. Binds with similar affinity to both methylated and non-methylated DNA. Highly distributive behavior on DNA substrates containing multiple 5-meC residues. Involved with Pol IV in the remodeling of the 5S rDNA chromatin via DNA methylation modifications during the first days of development post-germination. Participates in UV-B induced- and oxidative DNA damage repair (PubMed:24155752).^{[30] [31] [32] [33] [34] [35] [36] [37]}

References

1. ↑ Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:http://dx.doi.org/10.1006/jmbi.2001.4977
2. ↑ Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448-50. PMID:2247149 doi:http://dx.doi.org/10.1038/348448A0
3. ↑ Affara NA, Chalmers IJ, Ferguson-Smith MA. Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain. Hum Mol Genet. 1993 Jun;2(6):785-9. PMID:8353496
4. ↑ Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet. 1992 May;50(5):1008-11. PMID:1570829
5. ↑ Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet. 1992 Nov;51(5):979-84. PMID:1415266
6. ↑ Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471-4. PMID:1339396
7. ↑ Braun A, Kammerer S, Cleve H, Lohrs U, Schwarz HP, Kuhnle U. True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case. Am J Hum Genet. 1993 Mar;52(3):578-85. PMID:8447323
8. ↑ Jager RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet. 1992 Dec;90(4):350-5. PMID:1483689
9. ↑ Zeng YT, Ren ZR, Zhang ML, Huang Y, Zeng FY, Huang SZ. A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis. J Med Genet. 1993 Aug;30(8):655-7. PMID:8105086
10. ↑ Poulat F, Soullier S, Goze C, Heitz F, Calas B, Berta P. Description and functional implications of a novel mutation in the sex-determining gene SRY. Hum Mutat. 1994;3(3):200-4. PMID:8019555 doi:http://dx.doi.org/10.1002/humu.1380030305
11. ↑ Haqq CM, King CY, Ukiyama E, Falsafi S, Haqq TN, Donahoe PK, Weiss MA. Molecular basis of mammalian sexual determination: activation of Mullerian inhibiting substance gene expression by SRY. Science. 1994 Dec 2;266(5190):1494-500. PMID:7985018
12. ↑ Schmitt-Ney M, Thiele H, Kaltwasser P, Bardoni B, Cisternino M, Scherer G. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am J Hum Genet. 1995 Apr;56(4):862-9. PMID:7717397
13. ↑ Hiort O, Gramss B, Klauber GT. True hermaphroditism with 46,XY karyotype and a point mutation in the SRY gene. J Pediatr. 1995 Jun;126(6):1022. PMID:7776083
14. ↑ Scherer G, Held M, Erdel M, Meschede D, Horst J, Lesniewicz R, Midro AT. Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations. Cytogenet Cell Genet. 1998;80(1-4):188-92. PMID:9678356
15. ↑ Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Arnhold IJ, Bilharinho Mendonca B. A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum Genet. 1998 Feb;102(2):213-5. PMID:9521592
16. ↑ Dork T, Stuhrmann M, Miller K, Schmidtke J. Independent observation of SRY mutation I90M in a patient with complete gonadal dysgenesis. Hum Mutat. 1998;11(1):90-1. PMID:9450909 doi:<90::AID-HUMU14>3.0.CO;2-U 10.1002/(SICI)1098-1004(1998)11:1<90::AID-HUMU14>3.0.CO;2-U
17. ↑ Imai A, Takagi A, Tamaya T. A novel sex-determining region on Y (SRY) missense mutation identified in a 46,XY female and also in the father. Endocr J. 1999 Oct;46(5):735-9. PMID:10670762
18. ↑ Schaffler A, Barth N, Winkler K, Zietz B, Rummele P, Knuchel R, Scholmerich J, Palitzsch KD. Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab. 2000 Jun;85(6):2287-92. PMID:10852465
19. ↑ Canto P, de la Chesnaye E, Lopez M, Cervantes A, Chavez B, Vilchis F, Reyes E, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez JP. A mutation in the 5' non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism. J Clin Endocrinol Metab. 2000 May;85(5):1908-11. PMID:10843173
20. ↑ Okuhara K, Tajima T, Nakae J, Fujieda K. A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal. J Hum Genet. 2000;45(2):112-4. PMID:10721678 doi:10.1007/s100380050026
21. ↑ Jordan BK, Jain M, Natarajan S, Frasier SD, Vilain E. Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab. 2002 Jul;87(7):3428-32. PMID:12107262
22. ↑ Maier EM, Leitner C, Lohrs U, Kuhnle U. True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene. J Pediatr Endocrinol Metab. 2003 Apr-May;16(4):575-80. PMID:12793612
23. ↑ Gimelli G, Gimelli S, Dimasi N, Bocciardi R, Di Battista E, Pramparo T, Zuffardi O. Identification and molecular modelling of a novel familial mutation in the SRY gene implicated in the pure gonadal dysgenesis. Eur J Hum Genet. 2007 Jan;15(1):76-80. Epub 2006 Oct 25. PMID:17063144 doi:10.1038/sj.ejhg.5201719
24. ↑ Inoue H, Nomura M, Yanase T, Ichino I, Goto K, Ikuyama S, Takayanagi R, Nawata H. A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determining region Y chromosome-bearing cells in the gonads. Intern Med. 1998 May;37(5):467-71. PMID:9652903
25. ↑ Margarit E, Coll MD, Oliva R, Gomez D, Soler A, Ballesta F. SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite. Am J Med Genet. 2000 Jan 3;90(1):25-8. PMID:10602113
26. ↑ Ohe K, Lalli E, Sassone-Corsi P. A direct role of SRY and SOX proteins in pre-mRNA splicing. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1146-51. Epub 2002 Jan 29. PMID:11818535 doi:10.1073/pnas.022645899
27. ↑ Phillips NB, Nikolskaya T, Jancso-Radek A, Ittah V, Jiang F, Singh R, Haas E, Weiss MA. Sry-directed sex reversal in transgenic mice is robust with respect to enhanced DNA bending: comparison of human and murine HMG boxes. Biochemistry. 2004 Jun 8;43(22):7066-81. PMID:15170344 doi:10.1021/bi049920a
28. ↑ Li B, Phillips NB, Jancso-Radek A, Ittah V, Singh R, Jones DN, Haas E, Weiss MA. SRY-directed DNA bending and human sex reversal: reassessment of a clinical mutation uncovers a global coupling between the HMG box and its tail. J Mol Biol. 2006 Jul 7;360(2):310-28. Epub 2006 May 9. PMID:16762365 doi:S0022-2836(06)00522-5
29. ↑ Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:http://dx.doi.org/10.1006/jmbi.2001.4977
30. ↑ Gong Z, Morales-Ruiz T, Ariza RR, Roldan-Arjona T, David L, Zhu JK. ROS1, a repressor of transcriptional gene silencing in Arabidopsis, encodes a DNA glycosylase/lyase. Cell. 2002 Dec 13;111(6):803-14. doi: 10.1016/s0092-8674(02)01133-9. PMID:12526807 doi:http://dx.doi.org/10.1016/s0092-8674(02)01133-9
31. ↑ Morales-Ruiz T, Ortega-Galisteo AP, Ponferrada-Marin MI, Martinez-Macias MI, Ariza RR, Roldan-Arjona T. DEMETER and REPRESSOR OF SILENCING 1 encode 5-methylcytosine DNA glycosylases. Proc Natl Acad Sci U S A. 2006 May 2;103(18):6853-8. doi: , 10.1073/pnas.0601109103. Epub 2006 Apr 19. PMID:16624880 doi:http://dx.doi.org/10.1073/pnas.0601109103
32. ↑ Douet J, Blanchard B, Cuvillier C, Tourmente S. Interplay of RNA Pol IV and ROS1 during post-embryonic 5S rDNA chromatin remodeling. Plant Cell Physiol. 2008 Dec;49(12):1783-91. doi: 10.1093/pcp/pcn152. Epub 2008 , Oct 9. PMID:18845569 doi:http://dx.doi.org/10.1093/pcp/pcn152
33. ↑ Ponferrada-Marin MI, Roldan-Arjona T, Ariza RR. ROS1 5-methylcytosine DNA glycosylase is a slow-turnover catalyst that initiates DNA demethylation in a distributive fashion. Nucleic Acids Res. 2009 Jul;37(13):4264-74. doi: 10.1093/nar/gkp390. Epub 2009 , May 13. PMID:19443451 doi:http://dx.doi.org/10.1093/nar/gkp390
34. ↑ Ponferrada-Marin MI, Martinez-Macias MI, Morales-Ruiz T, Roldan-Arjona T, Ariza RR. Methylation-independent DNA binding modulates specificity of Repressor of Silencing 1 (ROS1) and facilitates demethylation in long substrates. J Biol Chem. 2010 Jul 23;285(30):23032-9. doi: 10.1074/jbc.M110.124578. Epub 2010 , May 19. PMID:20489198 doi:http://dx.doi.org/10.1074/jbc.M110.124578
35. ↑ Questa JI, Fina JP, Casati P. DDM1 and ROS1 have a role in UV-B induced- and oxidative DNA damage in A. thaliana. Front Plant Sci. 2013 Oct 21;4:420. doi: 10.3389/fpls.2013.00420. eCollection , 2013. PMID:24155752 doi:http://dx.doi.org/10.3389/fpls.2013.00420
36. ↑ Lee J, Jang H, Shin H, Choi WL, Mok YG, Huh JH. AP endonucleases process 5-methylcytosine excision intermediates during active DNA demethylation in Arabidopsis. Nucleic Acids Res. 2014 Oct;42(18):11408-18. doi: 10.1093/nar/gku834. Epub 2014 , Sep 16. PMID:25228464 doi:http://dx.doi.org/10.1093/nar/gku834
37. ↑ Hong S, Hashimoto H, Kow YW, Zhang X, Cheng X. The carboxy-terminal domain of ROS1 is essential for 5-methylcytosine DNA glycosylase activity. J Mol Biol. 2014 Nov 11;426(22):3703-3712. doi: 10.1016/j.jmb.2014.09.010. Epub , 2014 Sep 21. PMID:25240767 doi:http://dx.doi.org/10.1016/j.jmb.2014.09.010
38. ↑ Du X, Yang Z, Xie G, Wang C, Zhang L, Yan K, Yang M, Li S, Zhu JK, Du J. Molecular basis of the plant ROS1-mediated active DNA demethylation. Nat Plants. 2023 Feb;9(2):271-279. PMID:36624257 doi:10.1038/s41477-022-01322-8