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TP53 lacks tetramerization and N-terminal domains due to novel inactivating mutations detected in leukemia patients
Journal of Cancer Research and Therapeutics ( IF 1.4 ) Pub Date : 2021-07-01 , DOI: 10.4103/jcrt.jcrt_536_19 Yasir Hameed 1 , Samina Ejaz 1
Background: TP53 is a highly conserved tumor suppressor gene present on chromosome 17 and comprised 11 exons and 12 introns. The TP53 protein maintained the genomic integrity of the cell by regulating different pathways. The association of TP53 with leukemia and the increasing prevalence of leukemia in Pakistan instigated us to initiate the current study.
Materials and Methods: The TP53 gene of acute myeloid leukemia patients (n = 23) and normal individuals (n = 30) was amplified through polymerase chain reaction (PCR). The PCR amplified products of 3 samples 1 normal (NC-30) and 2 cancerous (LK-6 and LK-19) were subjected to deoxyribonucleic acid (DNA) sequence analysis. Bioinformatics analysis of the obtained DNA sequences helped to identify nature, type, and functional impact of mutations, if any.
Results: Results revealed 2 novel mutations in Case No. 1 (c. G >A10987 and c. InsA13298_13299) and Case No. 2 (c. InsC13284_13285, c. T >A13365) which generate a premature codon (ocher) at position 239 and lead to truncated TP53 protein. In Case No. 3, 16 novel mutations were identified and c. delC11093 mutation created a premature codon (opal) at 59th position. Hence, the resultant protein will lack its tetramerization and N-terminal domain required for its normal functioning. Moreover, some intronic mutations were noticed and found to have a negative impact on splicing related regulatory sequences.
Conclusion: Results suggest the role of TP53 inactivating mutations in pathogenesis of leukemia.
中文翻译：
由于在白血病患者中检测到新的失活突变，TP53 缺乏四聚体和 N 端结构域
背景： TP53是17号染色体上高度保守的抑癌基因，由11个外显子和12个内含子组成。TP53 蛋白通过调节不同的通路来维持细胞的基因组完整性。TP53 与白血病的关联以及巴基斯坦白血病患病率的增加促使我们开始了当前的研究。
材料与方法：急性髓性白血病患者（n = 23）和正常人（n= 30) 通过聚合酶链式反应 (PCR) 扩增。对1个正常（NC-30）和2个癌（LK-6和LK-19）样品的PCR扩增产物进行脱氧核糖核酸（DNA）序列分析。获得的 DNA 序列的生物信息学分析有助于识别突变的性质、类型和功能影响（如果有的话）。
结果：结果显示，案例 1（c.G >A10987 和 c.InsA13298_13299）和案例 2（c.InsC13284_13285，c.T >A13365）中有 2 个新突变，在第 239 位产生过早密码子（赭色）并导致截短的 TP53 蛋白。在第 3 号案例中，鉴定了 16 个新突变，并且 c．delC11093突变在第 59 位产生了一个早熟密码子（蛋白石）位置。因此，所得蛋白质将缺乏其正常功能所需的四聚体和 N 端结构域。此外，发现一些内含子突变对剪接相关调控序列有负面影响。
结论：结果提示TP53失活突变在白血病发病机制中的作用。
更新日期：2021-07-01
Journal of Cancer Research and Therapeutics ( IF 1.4 ) Pub Date : 2021-07-01 , DOI: 10.4103/jcrt.jcrt_536_19 Yasir Hameed 1 , Samina Ejaz 1
Affiliation
Background: TP53 is a highly conserved tumor suppressor gene present on chromosome 17 and comprised 11 exons and 12 introns. The TP53 protein maintained the genomic integrity of the cell by regulating different pathways. The association of TP53 with leukemia and the increasing prevalence of leukemia in Pakistan instigated us to initiate the current study.
Materials and Methods: The TP53 gene of acute myeloid leukemia patients (n = 23) and normal individuals (n = 30) was amplified through polymerase chain reaction (PCR). The PCR amplified products of 3 samples 1 normal (NC-30) and 2 cancerous (LK-6 and LK-19) were subjected to deoxyribonucleic acid (DNA) sequence analysis. Bioinformatics analysis of the obtained DNA sequences helped to identify nature, type, and functional impact of mutations, if any.
Results: Results revealed 2 novel mutations in Case No. 1 (c. G >A10987 and c. InsA13298_13299) and Case No. 2 (c. InsC13284_13285, c. T >A13365) which generate a premature codon (ocher) at position 239 and lead to truncated TP53 protein. In Case No. 3, 16 novel mutations were identified and c. delC11093 mutation created a premature codon (opal) at 59th position. Hence, the resultant protein will lack its tetramerization and N-terminal domain required for its normal functioning. Moreover, some intronic mutations were noticed and found to have a negative impact on splicing related regulatory sequences.
Conclusion: Results suggest the role of TP53 inactivating mutations in pathogenesis of leukemia.
中文翻译：
由于在白血病患者中检测到新的失活突变，TP53 缺乏四聚体和 N 端结构域
背景： TP53是17号染色体上高度保守的抑癌基因，由11个外显子和12个内含子组成。TP53 蛋白通过调节不同的通路来维持细胞的基因组完整性。TP53 与白血病的关联以及巴基斯坦白血病患病率的增加促使我们开始了当前的研究。
材料与方法：急性髓性白血病患者（n = 23）和正常人（n= 30) 通过聚合酶链式反应 (PCR) 扩增。对1个正常（NC-30）和2个癌（LK-6和LK-19）样品的PCR扩增产物进行脱氧核糖核酸（DNA）序列分析。获得的 DNA 序列的生物信息学分析有助于识别突变的性质、类型和功能影响（如果有的话）。
结果：结果显示，案例 1（c.G >A10987 和 c.InsA13298_13299）和案例 2（c.InsC13284_13285，c.T >A13365）中有 2 个新突变，在第 239 位产生过早密码子（赭色）并导致截短的 TP53 蛋白。在第 3 号案例中，鉴定了 16 个新突变，并且 c．delC11093突变在第 59 位产生了一个早熟密码子（蛋白石）位置。因此，所得蛋白质将缺乏其正常功能所需的四聚体和 N 端结构域。此外，发现一些内含子突变对剪接相关调控序列有负面影响。
结论：结果提示TP53失活突变在白血病发病机制中的作用。
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