ATM丝氨酸/苏氨酸激酶(ATM;以前称为共济失调-毛细血管扩张突变)在维持基因组稳定性和调节多个下游途径中起关键作用。比如DNA修复,细胞周期停滞,和凋亡。作为丝氨酸/苏氨酸激酶,ATM有一系列下游磷酸化底物,包括检查点效应子检查点激酶2(CHK2)。ATM通过磷酸化和激活CHK2抑制细胞周期进程,CHK2在肿瘤的形成和发展中起重要作用,并参与双链DNA断裂后的DNA修复反应。在这项研究中,我们使用最近开发的哺乳动物功能遗传筛选系统来探索一系列ATM底物及其在DNA损伤中的作用,以增强我们对DNA损伤反应的理解。Ubiquilin4(UBQLN4),属于泛素家族,其特征在于泛素样(UBL)和泛素相关(UBA)结构域,被确定为ATM的新底物。UBQLN4参与各种细胞内过程,如自噬成熟,P21法规,和运动型轴突形态发生。然而,UBQLN4的生物学功能尚待阐明。在这项研究中,我们不仅确定UBQLN4是ATM的底物,但也发现UBQLN4与抗凋亡蛋白Bcl-2相关蛋白A1(BCL2A1)和Bcl-2样蛋白10(BCL2L10)相互作用并稳定,并防止间皮瘤细胞因DNA损伤而凋亡。这些发现扩大了我们对UBQLN4在间皮瘤中的作用的理解,并为针对ATM底物的潜在间皮瘤治疗提供了新的见解。
ATM serine/threonine kinase (ATM; previously known as ataxia-telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double-stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (
UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, was identified as a new substrate for ATM.
UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of
UBQLN4 remains to be elucidated. In this study, we not only identified
UBQLN4 as a substrate for ATM, but also found that
UBQLN4 interacts with and stabilizes the anti-apoptotic proteins Bcl-2-related protein A1 (BCL2A1) and Bcl-2-like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of
UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM.