Functional Interplay of p53 and Mus81 in DNA Damage Responses and Cancer

Abstract

Mus81 plays an integral role in the maintenance of genome stability and DNA repair in mammalian cells. Deficiency of Mus81 in human and mouse cells results in hypersensitivity to interstrand cross-linking (ICL) agents and elevated levels of genomic instability. Furthermore, Mus81-mutant mice are susceptible to spontaneous lymphomas. The role of cellular checkpoints in mediating the phenotypes observed in Mus81-deficient cells and mice is currently unknown. In this study, we have observed increased activation of p53 in Mus81 Significantly, we show that loss of even a single allele of Mus81 drastically modifies the tumor spectrum of p53-mutant mice and increases their predisposition to developing sarcomas. Our results reveal a key role for p53 in mediating the response to spontaneous and ICL-induced DNA damage that occurs in the absence of Mus81. Furthermore, our data show that loss of Mus81, in addition to p53, is a key step in sarcoma development.

Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin

“…35 Mus81-deficient mouse embryonic fibroblasts displayed an elevated level of p53 in response to MMC, and p53 inactivation rescued the ICL sensitivity of Mus81-deficient cells at the expense of increased genomic instability. 36 In this study, our results evidenced an elevated expression of phosphorylated p53 in Mus81-suppressed MCF-7 cells after cisplatin treatment, but the Bcl-2 expression changed in the opposite direction. The results were consistent with the recent study in HCC cells.…”

Inactivation of Chk2 and Mus81 Leads to Impaired Lymphocytes Development, Reduced Genomic Instability, and Suppression of Cancer

“…Mice homozygous for the Mus81 Δex3-4 mutation showed no expression of Mus81 protein, and displayed elevated levels of spontaneous genomic instability and cancer predisposition [11]. While the cause for the lack of tumorigenesis in Mus81 Δex9-12 mutant mice is still not clear, inactivation of p53 in Mus81 Δex3-4/Δex3-4 mice rescued their MMC hypersensitivity and exacerbated their genomic instability and tumorigenesis [12].…”

Downregulation of Mus81 as a novel prognostic biomarker for patients with colorectal carcinoma

“…Moreover, Mus81 was found to interact with p53 and checkpoint genes such as Cds1 ⁄ chk2 and Rhp51 ⁄ Rad51. (17)(18)(19) Recently, Mus81 has also been shown to be required in the survival of telomerase-negative cancer cells by alternative lengthening of the telomeres pathway.(20) Also, the single nucleotide polymorphisms of Mus81 were found to be associated with an increased risk of developing breast cancer.(21) Although these studies have indicated the potential role of Mus81 in human malignancies, the evidence for its expression pattern in human malignancies is still limited. (22,23) In a previous study, we have documented the decrease of Mus81 expression in human hepatocellular carcinoma (HCC) tissues and its association with metastasis and poor prognosis, which provided the first evidence for the expression pattern and potential role of Mus81 in human malignancy.…”

“…Moreover, Mus81 was found to interact with p53 and checkpoint genes such as Cds1 ⁄ chk2 and Rhp51 ⁄ Rad51. (17)(18)(19) Recently, Mus81 has also been shown to be required in the survival of telomerase-negative cancer cells by alternative lengthening of the telomeres pathway. (20) Also, the single nucleotide polymorphisms of Mus81 were found to be associated with an increased risk of developing breast cancer.…”