Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres

Abstract

TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…Indeed, many hotspot mutations arm the mutant p53 with new weapons to promote cancer. Such activities, known as mutant p53 gain-of-function, are involved in regulation of various cancer hallmarks (Figure 3), including genomic instability [65–69], anti-apoptotic activities [70–79], replicative mortality [69, 80], invasion and metastasis [63, 64, 66, 67, 79, 81–91], angiogenesis [92–95], dysregulated metabolism [96–99], and tumor-related inflammation [100–103]. Mutant p53 gain-of-function can drive cancer through several potential mechanisms [104, 105]: (i) binding to structure-specific DNA to subsequently exert transcriptional regulation; (ii) interacting with transcription factors or cofactors to enhance or decease transcription of their targeted genes; (iii) associating with chromatin or the chromatin regulatory complex; and (iv) directly interacting with and influencing other proteins and their functions.…”

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

“…Two studies have reported that MSI+ cancers have shorter telomeres than MSI- cancers [13, 21]. Limited data are available on the association between telomere length and somatic mutation profiles such as changes in TP53 , KRAS and BRAF [22, 23]. …”

<p>Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma</p>

“…Several p53 missense mutations, including those two mutants in our study at codons R248 and R175, are among the most prevalent hotspot mutations in HPSCCs, occurring within the central region of the protein which serves as the p53 DNA-binding domain. [33][34][35][36] They both are localized in the cytoplasm as well where it can exert its "Gain of Function (GOF)" activity. Both mutant types not only lose p53WT'stranscriptional function but also have dominant-negative activity by heterodimerization with p53WT.…”