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Roles of Timeless in DNA repair and carcinogenesis

Year: 2021
Type: dissertation
Abstract: Timeless, an integral component of the replication fork protection complex, stabilizes the replication fork in response to DNA damage. Timeless is also involved with the maintenance of genomic integrity through its interaction with downstream targets that aid in checkpoint regulation, DNA repair, and DNA replication. Recent studies have shown that Timeless interacts with PARP1 to promote DNA repair via homologous recombination. Timeless also interacts with DDX11 to facilitate replication at hard-to-replicate regions of the genome. Studies have suggested the role of Timeless in cancer progression; Timeless is frequently overexpressed in various types of cancers, and this high expression is associated with poor patient prognosis and increased metastasis. Furthermore, Timeless confers resistance to chemotherapeutic drugs such as cisplatin and serves as a marker for tamoxifen resistance. However, the mechanisms by which Timeless regulates DNA repair and carcinogenesis are not well understood. In this study, we aimed to understand the role of Timeless in genome maintenance and cancer phenotypes. We performed mutational analysis of Timeless to determine the role of Timeless-PARP1 interaction in DNA repair and Timeless-DDX11 interaction in DNA replication. We found that Timeless depletion leads to growth inhibition and a significant increase in senescence-associated phenotypes. Considering that senescence is generally regarded as a tumor-suppressive mechanism, our findings suggest that Timeless promote survival of cancer cells. Future studies would include assessing the effects of Timeless mutations in DNA replication, repair, and cancer phenotypes. We expect that these studies will serve as a stepping-stone to develop effective strategies for cancer therapy.
DOI: 10.17918/00000848
Language: English
Open Access status: gold
OpenAlex ID: W4212929258
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