Distribution of FEN1 mediated by TM9SF1: unraveling the potential mechanisms of DNA damage

Abstract

Abstract Transmembrane 9 superfamily protein member 1 (TM9SF1) has abnormal overexpression in specific clinical diseases; however, its precise role in disease progression remains poorly understood. The current study revealed the critical importance of maintaining appropriate TM9SF1 levels for the proper distribution of FEN1, a protein crucial for DNA repair. TM9SF1 interacted with FEN1 through its N-terminal region spanning amino acids 1-236, which could translocate into the nucleus, while the C-terminal segment spanning amino acids 237–606 was responsible for the cellular localization of TM9SF1. Overexpression of TM9SF1 led to the sequestration of FEN1 in the cytoplasm, thus hindering FEN1’s entry into the nucleus. Consequently, DNA repair capacity was compromised, leading to increased DNA damage and subsequently cell growth inhibition. Moreover, TM9SF1 knockdown in 293T cells or its knockout in mouse kidney cells did not affect the expression levels and distribution of FEN1 or DNA damage induction. The current study revealed the mechanism of the abnormally high TM9SF1 expression in the occurrence and development of clinical diseases, thus positioning TM9SF1 as a potential drug target.