Each cell in the human body receives thousands of DNA lesions per day. To counteract risks posed by DNA damage, cells have evolved a signaling network called the DNA-damage response (DDR). This mechanism allows cells to sense DNA lesions, signal their presence and promote their repair. Inherited mutations in DNA repair genes are associated with predisposition to cancer. Moreover, defects in DDR components in early neoplastic lesions of sporadic tumors allow cancer progression.
Nucleoporins, proteins localized at the nuclear envelope, have been linked to various human diseases such as neurological disorders, autoimmune dysfunctions, and cancer. Nucleoporin TPR (Translocated Promoter Region) was previously linked to cancer since its N- terminal domain has been found fused with the protein kinase domains of various proto- oncogenes such as RAF and MET resulting in solid human tumors. TPR expression level was found deregulated in many types of human tumors such as breast and liver cancer. Importantly, amplification of TPR gene is associated with shorter survival in cancer patients, e.g. those with pediatric ependymomas (3rd most common brain tumor in children). All these findings support a critical role for TPR in the mechanism of oncogenesis and provide the prospect for accurate diagnosis and targeted cancer therapy in the future.
Importantly, although nucleoporin TPR was previously identified as one of the proteins activated in response to DNA damage, its potential role in the maintenance of genomic integrity is unknown.
The overall aim of the project was to characterize molecular crosstalk mechanism between the DNA-damage response network and nuclear envelope, which contributes to the maintenance of genome stability and prevents cancer development.
