The Effects of two TP53 Polymorphisms on Its Expression and Folding and Association with the Pathogenesis of Polycystic Ovary Syndrome: in-silico analysis
-
Mahboobeh Sabeti Akbar-Abad
,
Hossein Shahriari
,
Mahdi Majidpour
,
Razieh Akhtar
,
Ramin Saravani
,
Mehdi Zandhaghighi
,
Khodadad Sheikhzadeh
Abstract
Objectives: Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy characterized by various reproductive and metabolic abnormalities. The tumor suppressor p53 (TP53) plays a crucial role in cellular stress responses. Alterations in its structure or expression can influence PCOS pathogenesis. This study investigates the association of two genetic variants, rs2287499 and rs1042522, with the expression levels and folding stability of TP53 protein through in-silico analyses.
Methods: Utilizing bioinformatics tools, we examined the potential impacts of these single nucleotide polymorphisms (SNPs) on TP53 transcriptional activity, protein structure, and functional integrity.
Results: Our findings indicate that the rs2287499 variant significantly influences TP53 expression levels, while rs1042522 is associated with altered protein folding dynamics. These changes may disrupt TP53's normal regulatory functions, contributing to PCOS etiology. Furthermore, our study establishes a framework for integrating genetic variants into the understanding of TP53-mediated mechanisms in PCOS, which could pave the way for developing targeted therapeutic strategies.
Conclusion: These results underscore the importance of genetic variants in PCOS hormonal and metabolic dysregulation.
1. Biglari-Zadeh G, Sargazi S, Mohammadi M, Ghasemi M, Majidpour M, Saravani R, Mirinejad S. Relationship Between Genetic Polymorphisms in Cell Cycle Regulatory Gene TP53 and Polycystic Ovarian Syndrome: A Case–Control Study and In Silico Analyses. Biochem Genet. 2023:1-23. https://doi.org/10.1007/s10528-023-10349-1
2. Sabeti Akbar-Abad M, Majidpour M, Sargazi S, Ghasemi M, Saravani R. Unraveling the Role of Cathepsin B Variants in Polycystic Ovary Syndrome: Insights from a Case-Control Study and Computational Analyses. Reprod Sci. 2025;32(4):1166-79. https://doi.org/10.1007/s43032-025-01806-w.
3. Govahi Kakhki F, Sargazi S, Montazerifar F, Majidpour M, Karajibani A, Karajibani M, Ghasemi M. IGF2BP2 and IGFBP3 Genotypes, Haplotypes, and Genetic Models Studies in Polycystic Ovary Syndrome. J Clin Lab Anal. 2024;38(5):e25021. https://doi.org/10.1002/jcla.25021.
4. Majidpour M, Sargazi S, Ghasemi M, Sabeti Akbar-Abad M, Sarhadi M, Saravani R. LncRNA MEG3, GAS5, and HOTTIP polymorphisms association with risk of polycystic ovary syndrome: a case–control study and computational analyses. Biochem Genet. 2024:1-23. https://doi.org/10.1007/s10528-024-10977-1.
5. Bathaie SZ, Ashraf M, Azizian M, Khademian N, Abroun S. Crocetin regulates cell cycle progression in N-nitroso-Nmethylurea (NMU)-induced breast cancer in rat: cyclin D1 suppression, p21Cip1 and p53 induction. Acta Biochim Iran. 2024. https://doi.org/10.18502/abi.v2i1.16244.
6. Zanjirband M, Hodayi R, Safaeinejad Z, Nasr-Esfahani M, Ghaedi-Heydari R. Evaluation of the p53 pathway in polycystic ovarian syndrome pathogenesis and apoptosis enhancement in human granulosa cells through transcriptome data analysis. Sci Rep. 2023;13(1):11648. https://doi.org/10.1038/s41598-023-38340-1.
7. Rakhshanizade N, Sargazi S, Karajibani M, Majidpour M, Karajibani A, Montazerifar F, Ghasemi M. Influence of Suppressor of Cytokine Signaling 1 (SOCS1) Gene Variations on Polycystic Ovary Syndrome. Indian J Clin Biochem. 2024:1-10. https://doi.org/10.1007/s12291-024-01248-2.
8. Wang C, Tan JYM, Chitkara N, Bhatt S. TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications. Cancers (Basel). 2024;16(17):3069. https://doi.org/10.3390/cancers16173069.
9. Taghizadeh N, Mohammadi S, Saeedi V, Haghighi L, Nourbakhsh M, Nourbakhsh M, Azar MR. Association between steroid hormones and insulin resistance in patients with polycystic ovary syndrome. Acta Biochim Iran. 2023. https://doi.org/10.18502/abi.v1i1.14062.
10. Saito A, Omura I, Imaizumi K. CREB3L1/OASIS: cell cycle regulator and tumor suppressor. FEBS J. 2024;291(22):4853-66. https://doi.org/10.1111/febs.17052.
11. Asma K, Akram Vatannejad V, Sara B, Maryam T, Molood B, Farzad A, et al. Association of Homocysteine with body mass index in women with polycystic ovary Syndrome. Acta Biochim Iran. 2025;3(1). https://doi.org/10.18502/abi.v3i1.19346.
12. Huszno J, Grzybowska E. TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer. Oncology letters. 2018;16(1):34-40. https://doi.org/10.3892/ol.2018.8627.
13. Biglari-Zadeh G, Sargazi S, Mohammadi M, Ghasemi M, Majidpour M, Saravani R, Mirinejad S. Relationship between genetic polymorphisms in Cell Cycle Regulatory Gene TP53 and polycystic ovarian syndrome: a case–control study and in Silico Analyses. Biochemical Genetics. 2023;61(5):1827-49, 10.007/s10528-023-349-1. https://doi.org/10.1007/s10528-023-10349-1.
14. Naidoo P, Maharaj AB, Ghazi T, Chuturgoon AA. MTHFR C677T rs1801133 and TP53 Pro72Arg rs1042522 gene variants in South African Indian and Caucasian psoriatic arthritis patients. Genet Mol Biol. 2025;48(1):e20230325. https://doi.org/10.1590/1678-4685-GMB-2023-0325.
15. Siddamalla S, Reddy TV, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M. Influence of tumour suppressor gene (TP53, BRCA1 and BRCA2) polymorphisms on polycystic ovary syndrome in South Indian women. Eur J Obstet Gynecol Reprod Biol. 2018;227:13-8. https://doi.org/10.1016/j.ejogrb.2018.05.027
16. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. Journal of molecular graphics. 1996;14(1):33-8, 27-8. https://doi.org/10.1016/0263-7855(96)00018-5.
17. Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome research. 2004;14(6):1188-90. https://doi.org/10.1101/gr.849004.
18. Farré D, Roset R, Huerta M, Adsuara JE, Roselló L, Albà MM, Messeguer X. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31(13):3651-3. https://doi.org/10.1093/nar/gkg605.
19. Huang X, Wu F, Zhang Z, Shao Z. Association between TP53 rs1042522 gene polymorphism and the risk of malignant bone tumors: a meta-analysis. Bioscience Reports. 2019;39(3):BSR20181832. https://doi.org/10.1042/BSR20181832.
20. Babu G, Bin Islam S, Khan MA. A review on the genetic polymorphisms and susceptibility of cancer patients in Bangladesh. Mol Biol Rep. 2022;49(7):6725-39. https://doi.org/10.1007/s11033-022-07282-8.
21. Rahman MA. Study of p53 gene polymorphism and risk of hepatocellular carcinoma: in a Bangladeshi cohort: © University of Dhaka; 2023.
22. Ahmed S, Safwat G, Moneer MM, El Ghareeb A, El Sherif AA, Loutfy SA. Prevalence of TP53 gene Pro72Arg (rs1042522) single nucleotide polymorphism among Egyptian breast cancer patients. Egypt J Med Hum Genet. 2023;24(1):24. https://doi.org/10.1186/s43042-023-00405-1.
23. An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell. 2004;117(6):735-48. https://doi.org/10.1016/j.cell.2004.05.009.
24. Qin B, Minter-Dykhouse K, Yu J, Zhang J, Liu T, Zhang H, et al. DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep. 2015;10(8):1324-34. https://doi.org/10.1016/j.celrep.2015.01.066
25. Repenning A, Happel D, Bouchard C, Meixner M, Verel-Yilmaz Y, Raifer H, et al. PRMT1 promotes the tumor suppressor function of p14(ARF) and is indicative for pancreatic cancer prognosis. The EMBO journal. 2021;40(13):e106777. https://doi.org/10.15252/embj.2020106777.
26. Restelli M, Magni M, Ruscica V, Pinciroli P, De Cecco L, Buscemi G, et al. A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation. Cell Death Dis. 2016;7(11):e2453-e. https://doi.org/ 10.1038/cddis.2016.359
27. Tan M, Cheng Y, Zhong X, Yang D, Jiang S, Ye Y, et al. LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway. Aging (Albany NY). 2021;13(3):4617-33. https://doi.org/10.18632/aging.202421.
28. Song WJ, Shi X, Zhang J, Chen L, Fu SX, Ding YL. Akt-mTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome. Gynecol Obstet Invest. 2018;83(2):124-32. https://doi.org/10.1159/000464351.
29. Boisvert F-M, Rhie A, Richard S, Doherty AJ. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity. Cell Cycle. 2005;4(12):1834-41. https://doi.org/10.4161/cc.4.12.2250.
30. Rashidi BH, Mohammad Hosseinzadeh F, Alipoor E, Asghari S, Yekaninejad MS, Hosseinzadeh-Attar MJ. Effects of Selenium Supplementation on Asymmetric Dimethylarginine and Cardiometabolic Risk Factors in Patients with Polycystic Ovary Syndrome. Biol Trace Elem Res. 2020;196(2):430-7. https://doi.org/10.1007/s12011-019-01954-6.
31. Celestino J, Chaves R, Matos M, Silva MSJ, Bruno J, Maia-Júnior J, Figueiredo J. Mechanisms of atresia in ovarian follicles. Anim Reprod. 2018;6(4):495-508.
32. Otsuka I. Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations. Int J Mol Sci. 2021;22(9):4409. https://doi.org/10.3390/ijms22094409.
33. Jiang Z, Zhu L. Update on molecular mechanisms of corticosteroid resistance in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2016;37:1-8. https://doi.org/10.1016/j.pupt.2016.01.002.
34. Anderson G. Polycystic Ovary Syndrome Pathophysiology: Integrating Systemic, CNS and Circadian Processes. Frontiers in bioscience (Landmark edition). 2024;29(1):24. https://doi.org/10.31083/j.fbl2901024.
35. Narani MS, Vatannejad A, Kheirollahi A, Teimouri M, Bayat S, Jadidzadeh F. Changes of biochemical parameters in normal weight and overweight/obese women with polycystic ovary Syndrome. Acta Biochim Iran. 2023. https://doi.org/10.18502/abi.v1i3.14547
36. Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, et al. Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance. Life sciences. 2019;232:116681. https://doi.org/10.1016/j.lfs.2019.116681.
2. Sabeti Akbar-Abad M, Majidpour M, Sargazi S, Ghasemi M, Saravani R. Unraveling the Role of Cathepsin B Variants in Polycystic Ovary Syndrome: Insights from a Case-Control Study and Computational Analyses. Reprod Sci. 2025;32(4):1166-79. https://doi.org/10.1007/s43032-025-01806-w.
3. Govahi Kakhki F, Sargazi S, Montazerifar F, Majidpour M, Karajibani A, Karajibani M, Ghasemi M. IGF2BP2 and IGFBP3 Genotypes, Haplotypes, and Genetic Models Studies in Polycystic Ovary Syndrome. J Clin Lab Anal. 2024;38(5):e25021. https://doi.org/10.1002/jcla.25021.
4. Majidpour M, Sargazi S, Ghasemi M, Sabeti Akbar-Abad M, Sarhadi M, Saravani R. LncRNA MEG3, GAS5, and HOTTIP polymorphisms association with risk of polycystic ovary syndrome: a case–control study and computational analyses. Biochem Genet. 2024:1-23. https://doi.org/10.1007/s10528-024-10977-1.
5. Bathaie SZ, Ashraf M, Azizian M, Khademian N, Abroun S. Crocetin regulates cell cycle progression in N-nitroso-Nmethylurea (NMU)-induced breast cancer in rat: cyclin D1 suppression, p21Cip1 and p53 induction. Acta Biochim Iran. 2024. https://doi.org/10.18502/abi.v2i1.16244.
6. Zanjirband M, Hodayi R, Safaeinejad Z, Nasr-Esfahani M, Ghaedi-Heydari R. Evaluation of the p53 pathway in polycystic ovarian syndrome pathogenesis and apoptosis enhancement in human granulosa cells through transcriptome data analysis. Sci Rep. 2023;13(1):11648. https://doi.org/10.1038/s41598-023-38340-1.
7. Rakhshanizade N, Sargazi S, Karajibani M, Majidpour M, Karajibani A, Montazerifar F, Ghasemi M. Influence of Suppressor of Cytokine Signaling 1 (SOCS1) Gene Variations on Polycystic Ovary Syndrome. Indian J Clin Biochem. 2024:1-10. https://doi.org/10.1007/s12291-024-01248-2.
8. Wang C, Tan JYM, Chitkara N, Bhatt S. TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications. Cancers (Basel). 2024;16(17):3069. https://doi.org/10.3390/cancers16173069.
9. Taghizadeh N, Mohammadi S, Saeedi V, Haghighi L, Nourbakhsh M, Nourbakhsh M, Azar MR. Association between steroid hormones and insulin resistance in patients with polycystic ovary syndrome. Acta Biochim Iran. 2023. https://doi.org/10.18502/abi.v1i1.14062.
10. Saito A, Omura I, Imaizumi K. CREB3L1/OASIS: cell cycle regulator and tumor suppressor. FEBS J. 2024;291(22):4853-66. https://doi.org/10.1111/febs.17052.
11. Asma K, Akram Vatannejad V, Sara B, Maryam T, Molood B, Farzad A, et al. Association of Homocysteine with body mass index in women with polycystic ovary Syndrome. Acta Biochim Iran. 2025;3(1). https://doi.org/10.18502/abi.v3i1.19346.
12. Huszno J, Grzybowska E. TP53 mutations and SNPs as prognostic and predictive factors in patients with breast cancer. Oncology letters. 2018;16(1):34-40. https://doi.org/10.3892/ol.2018.8627.
13. Biglari-Zadeh G, Sargazi S, Mohammadi M, Ghasemi M, Majidpour M, Saravani R, Mirinejad S. Relationship between genetic polymorphisms in Cell Cycle Regulatory Gene TP53 and polycystic ovarian syndrome: a case–control study and in Silico Analyses. Biochemical Genetics. 2023;61(5):1827-49, 10.007/s10528-023-349-1. https://doi.org/10.1007/s10528-023-10349-1.
14. Naidoo P, Maharaj AB, Ghazi T, Chuturgoon AA. MTHFR C677T rs1801133 and TP53 Pro72Arg rs1042522 gene variants in South African Indian and Caucasian psoriatic arthritis patients. Genet Mol Biol. 2025;48(1):e20230325. https://doi.org/10.1590/1678-4685-GMB-2023-0325.
15. Siddamalla S, Reddy TV, Govatati S, Guruvaiah P, Deenadayal M, Shivaji S, Bhanoori M. Influence of tumour suppressor gene (TP53, BRCA1 and BRCA2) polymorphisms on polycystic ovary syndrome in South Indian women. Eur J Obstet Gynecol Reprod Biol. 2018;227:13-8. https://doi.org/10.1016/j.ejogrb.2018.05.027
16. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. Journal of molecular graphics. 1996;14(1):33-8, 27-8. https://doi.org/10.1016/0263-7855(96)00018-5.
17. Crooks GE, Hon G, Chandonia JM, Brenner SE. WebLogo: a sequence logo generator. Genome research. 2004;14(6):1188-90. https://doi.org/10.1101/gr.849004.
18. Farré D, Roset R, Huerta M, Adsuara JE, Roselló L, Albà MM, Messeguer X. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31(13):3651-3. https://doi.org/10.1093/nar/gkg605.
19. Huang X, Wu F, Zhang Z, Shao Z. Association between TP53 rs1042522 gene polymorphism and the risk of malignant bone tumors: a meta-analysis. Bioscience Reports. 2019;39(3):BSR20181832. https://doi.org/10.1042/BSR20181832.
20. Babu G, Bin Islam S, Khan MA. A review on the genetic polymorphisms and susceptibility of cancer patients in Bangladesh. Mol Biol Rep. 2022;49(7):6725-39. https://doi.org/10.1007/s11033-022-07282-8.
21. Rahman MA. Study of p53 gene polymorphism and risk of hepatocellular carcinoma: in a Bangladeshi cohort: © University of Dhaka; 2023.
22. Ahmed S, Safwat G, Moneer MM, El Ghareeb A, El Sherif AA, Loutfy SA. Prevalence of TP53 gene Pro72Arg (rs1042522) single nucleotide polymorphism among Egyptian breast cancer patients. Egypt J Med Hum Genet. 2023;24(1):24. https://doi.org/10.1186/s43042-023-00405-1.
23. An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell. 2004;117(6):735-48. https://doi.org/10.1016/j.cell.2004.05.009.
24. Qin B, Minter-Dykhouse K, Yu J, Zhang J, Liu T, Zhang H, et al. DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep. 2015;10(8):1324-34. https://doi.org/10.1016/j.celrep.2015.01.066
25. Repenning A, Happel D, Bouchard C, Meixner M, Verel-Yilmaz Y, Raifer H, et al. PRMT1 promotes the tumor suppressor function of p14(ARF) and is indicative for pancreatic cancer prognosis. The EMBO journal. 2021;40(13):e106777. https://doi.org/10.15252/embj.2020106777.
26. Restelli M, Magni M, Ruscica V, Pinciroli P, De Cecco L, Buscemi G, et al. A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation. Cell Death Dis. 2016;7(11):e2453-e. https://doi.org/ 10.1038/cddis.2016.359
27. Tan M, Cheng Y, Zhong X, Yang D, Jiang S, Ye Y, et al. LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway. Aging (Albany NY). 2021;13(3):4617-33. https://doi.org/10.18632/aging.202421.
28. Song WJ, Shi X, Zhang J, Chen L, Fu SX, Ding YL. Akt-mTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome. Gynecol Obstet Invest. 2018;83(2):124-32. https://doi.org/10.1159/000464351.
29. Boisvert F-M, Rhie A, Richard S, Doherty AJ. The GAR motif of 53BP1 is arginine methylated by PRMT1 and is necessary for 53BP1 DNA binding activity. Cell Cycle. 2005;4(12):1834-41. https://doi.org/10.4161/cc.4.12.2250.
30. Rashidi BH, Mohammad Hosseinzadeh F, Alipoor E, Asghari S, Yekaninejad MS, Hosseinzadeh-Attar MJ. Effects of Selenium Supplementation on Asymmetric Dimethylarginine and Cardiometabolic Risk Factors in Patients with Polycystic Ovary Syndrome. Biol Trace Elem Res. 2020;196(2):430-7. https://doi.org/10.1007/s12011-019-01954-6.
31. Celestino J, Chaves R, Matos M, Silva MSJ, Bruno J, Maia-Júnior J, Figueiredo J. Mechanisms of atresia in ovarian follicles. Anim Reprod. 2018;6(4):495-508.
32. Otsuka I. Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations. Int J Mol Sci. 2021;22(9):4409. https://doi.org/10.3390/ijms22094409.
33. Jiang Z, Zhu L. Update on molecular mechanisms of corticosteroid resistance in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2016;37:1-8. https://doi.org/10.1016/j.pupt.2016.01.002.
34. Anderson G. Polycystic Ovary Syndrome Pathophysiology: Integrating Systemic, CNS and Circadian Processes. Frontiers in bioscience (Landmark edition). 2024;29(1):24. https://doi.org/10.31083/j.fbl2901024.
35. Narani MS, Vatannejad A, Kheirollahi A, Teimouri M, Bayat S, Jadidzadeh F. Changes of biochemical parameters in normal weight and overweight/obese women with polycystic ovary Syndrome. Acta Biochim Iran. 2023. https://doi.org/10.18502/abi.v1i3.14547
36. Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, et al. Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance. Life sciences. 2019;232:116681. https://doi.org/10.1016/j.lfs.2019.116681.
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| Issue | Vol 3 No 3 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| TP53 PCOS Bioinformatics rs1042522 rs2287499 | ||
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How to Cite
1.
Sabeti Akbar-Abad M, Shahriari H, Majidpour M, Akhtar R, Saravani R, Zandhaghighi M, Sheikhzadeh K. The Effects of two TP53 Polymorphisms on Its Expression and Folding and Association with the Pathogenesis of Polycystic Ovary Syndrome: in-silico analysis. ABI. 2025;3(3):155-161.
