A research team of Prof. Bae Jee-hyeon of College of Pharmacy and Prof. Lee Kang-seok, Kim Keun-pil and Kim Han-yong of Department of Life Science has identified a molecular signaling mechanism that determines the repair pathways of DNA double-strand breaks (DSB) causing serious damage to genomes. The research results were published in top international journal Nature Communications.
Living organisms are constantly exposed to various harmful environments that cause damage to genomic DNA. If such damage is not corrected in a timely manner, permanent damage occurs in genes, ultimately causing various diseases including cancer. Fortunately, human cells repair damage in DNAs constantly by using one of the following two pathways: Nonhomologous End Joining (NHEJ) and Homologous Recombination (HR). However, it has not been identified how human cells choose between the two pathways for DNA repair.
The research team discovered that FOXL2, an evolutionarily well-conserved transcriptional factor, is the key molecular cue that determines which pathway will be used for DNA repair as it directs DSB repair pathway choice by acetylation-dependent binding to Ku, a dimeric protein complex that initiates NHEJ.
In particular, when DNA double-strand break occurs, SIRT1 that catalyzes protein deacetylation reactions detects it and moves into the nucleus to deacetylate FOXL2, making it no longer able to bind to the Ku complex. Then the Ku complex can move freely to any point on DNA that needs to be repaired and initiate NHEJ.
By contrast, under normal circumstances, acetylated FOXL2 initiates HR repair while forming a strong binding with the Ku complex to prevent NHEJ. It is highly meaningful that the research team has unveiled the mechanism of this common biological phenomenon.
In particular, genetic mutation of FOXL2 is known to cause Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome (BPES) that could induce cancer, facial deformities and early menopause. The research team has proved that FOXL2 mutations cannot repair DNAs as FOXL2 inhibits Ku heterodimer formation. It is expected that the newly identified mechanism will be used to develop cures for various diseases including genetic disorders and cancer.
Source: Chung-Ang University