Topoisomerase-II mediated DNA damage: role of BRCA1 and other chromatin structure regulators
Year: 2009
Type: dissertation
Abstract: DNA topoisomerases are essential to the resolution of DNA topology during several metabolic processes such as transcription, replication and chromosome segregation. Topoisomerase II (TOP2) catalyzes the passage of one DNA double strand through another and that is the reason why this enzyme can (un)knot or (de)catenate DNA molecules. In mammals there are two isoforms of TOP2, α and β, which are encoded by separate genes. Given their vital functions TOP2 enzymes are a main target of anticancer drugs. Poisons, such as etoposide and doxorubicin, cause DNA double-strand breaks which assault DNA integrity and need to be properly repaired to guarantee genomic stability. The repair of these DNA lesions, either by homologous recombination or non-homologous end joining, will be triggered by the DNA damage response (DDR) in which BRCA1 is one of the key players. Senescence and apoptosis can also be signaled through the DDR, acting as barriers to neoplastic progression. Senescent cells undergo several changes not only in morphology but also in gene expression. Here, we provide evidence that BRCA1 role in the DDR also relates to the cellular fate given that BRCA1 depletion leads to an increase in the senescent outcome following exposure to TOP2 poisons. We also found evidence for etoposide-induced alteration of heterochromatin composition and distribution, namely altered levels of tri-methylated histone H3 at Lysine 9 (H3K9 me3) and heterochromatin protein 1α. Future studies shall address whether BRCA1 facilitates the senescent outcome via chromatin alteration.
Author: Inês Teles Alves
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W196060646