**7.** *TP53***: function and the consequence of its mutations in ovarian cancers**

The *TP53* gene is a tumour suppressor gene located on the short arm of chromosome 17 and contains 11 exons that encode for 53 kDa phosphoprotein (*TP53* protein), a transcription factor of genes responsible for cell cycle arrest and apoptosis. It is a nuclear transcriptional factor that upon binding to the nucleic acid component of the cell, it facilitates the regulation of several cellular processes through the control of several expression genes to maintain overall genome integrity and homeostasis [36].

Following deoxyribonucleic acid (DNA) damage, the *TP53* gene initiates the activation of DNA repair proteins by arresting cell growth by holding the cell cycle at the G1/S transitioning phase. This allows DNA repairs and the initiation of apoptosis on cells with irreparable DNA damage [37]. The activation of *TP53* function has been associated with numerous carcinogenesis-inducing stimuli which induce DNA damage such as Gamma or UV irradiation, nucleolar or ribosomal stress, hypoxia, inappropriate activation of proto-oncogenes and mitogenic signalling among others [38–40]. Once initiated, the *TP53* through the promotion of expression of the necessary genes responsible for cellular damage regulatory activities, where appropriate initiates cell cycle arrest, cellular senescence and differentiation, and cell death [41, 42]. For example, upon DNA damage, the *TP53* protein binds to the damaged DNA and stimulates another cell cycle regulatory gene (CDKN1A) to produce *p21* protein which interacts and forms a complex with cyclin-dependent kinase 2 (*CDK2),* a cell division-stimulating protein [43]. The formed *CDKN1A-CDK2* complex arrests the affected cell and stopped its progression past the G1- phase of the cell cycle and induces cellular senescence [41, 42, 44]. This *TP53* dependent blocking of cellular proliferation contributes to the prevention of cell transformation and tumour progression by triggering programmed cell death either by apoptosis or ferroptosis [36, 45]. However, an aberration in the *TP53* gene might result in the cessation of its cell cycle regulation and promotes carcinogenesis [46]. Therefore, these anti-tumour functions of *TP53* on DNA-damaged cells could be utilized for the development of anticancer drugs and appropriate management strategies.

*TP53* is one of the most frequently mutated genes in human cancer with more than 50% of human cancer types associated with its mutations [47]. This is because of its essential role in DNA damage-induced cellular regulation and tumour suppression. There are over 36,000 *TP53* mutations identified of which approximately 80% of them are missense mutations with amino acid substitution [47]. According to IARC *TP53* Database, 6.5% of the identified *TP53* mutations have been reported

to be associated with ovarian cancer of which approximately 70% of them are of the missense mutation subtypes while others include point and null mutations. Many of the missense mutations occurred at specific residues in the DNA binding domain which suggests a feature of selectivity peculiar to these mutants (http:// www-TP53.iarc.fr/).

The mechanism underlying the development and progression of ovarian cancers as it relates to *TP53* mutation has been extensively studied. However, it is not well understood and researchers have suggested possible ways of its action. For example, one mechanism explored by researchers is the gain of function property. Mutant *TP53* acquires a "gain of function" property that favours ovarian cancer progressive activities that may manifest as acquired resistance to chemotherapy, enhanced invasiveness which positively increased metastatic capabilities and down-regulation of certain metabolic pathways among others [48]. The gain of function property of the mutant *TP53* can be observed in the abrogation of function upon interaction with its family members such as *p63* and *p73*. They both can form complexes with the Wildtype *TP53* and serve the tumour suppressor functions in cells [49]. However, mutant *TP53* with a gain of function property has been reported to form a complex with phosphorylated *p63* which prevents the Wild-type *p63* natural function of tumour suppression, and at the same time induces the activation of certain oncogenic genes such as Cyclin G2 and Dicer [50–52]. Similarly, a study reported that mutant *TP53* directly binds to Wild-type *p73* and as a result, it prevents the inactivation of PDGFβ- the natural function of the *p73*- which subsequently favours invasiveness and metastasis [53]. Another possible mechanism of mutant *TP53*-induced ovarian carcinogenesis may be associated with protein aggregation [54]. This is because the *TP53* mutants especially of the missense subtype category have been reported to induce structural changes which potentially expose adhesion molecules that can co-aggregate with the Wild-type *TP53* or any of its family members causing trans- or cis-DN effects on the Wild-types *TP53* and its analogues [54–56]. This can explain the reason certain ovarian cancers present with an aggregation phenotype and as such, they are considered aggregation-associated diseases by some scholars. In light of the aforementioned possible mechanisms by which mutant *TP53* aid in the development and progression of ovarian cancer, and the near 100% prevalence of this mutation in the high-grade serous ovarian cancer- the most prevalent type of ovarian cancer- type, it can be deduced that the *TP53* mutation in ovarian cancers presents with an opportunity worthy of exploring in therapeutic interventions and inhibition studies.
