美国科罗拉多大学波尔德分校Roy Parker等研究人员合作发现，
据研究人员介绍，3′到5′RNA外切酶USB1的突变导致皮肤异色病伴中性粒细胞减少症（PN）的造血失败。虽然已知USB1能调节U6小核糖核酸的成熟，但PN的分子机制仍未确定，因为患者的前mRNA剪接未受影响。
研究人员产生了携带USB1的PN相关突变c.531_delA的人类胚胎干细胞，并显示该突变损害了人类的造血功能。在血液发育过程中，USB1突变体中的microRNA（miRNA）水平失调，导致了造血功能的衰竭，因为它不能去除由PAPD5/7添加的3′端腺苷酸尾巴。通过对PAPD5/7的遗传或化学抑制来调控miRNA的3′端腺苷化，可以挽救USB1突变体的造血功能。这项工作表明，USB1是一种miRNA去腺苷化酶，并建议将PAPD5/7的抑制作为PN的一种潜在疗法。
附：英文原文
Title: USB1 is a miRNA deadenylase that regulates hematopoietic development
Author: Ho-Chang Jeong, Siddharth Shukla, Wilson Chun Fok, Thao Ngoc Huynh, Luis Francisco Zirnberger Batista, Roy Parker
Issue&Volume: 2023-03-03
Abstract: Mutations in the 3′ to 5′ RNA exonuclease USB1 cause hematopoietic failure in poikiloderma with neutropenia (PN). Although USB1 is known to regulate U6 small nuclear RNA maturation, the molecular mechanism underlying PN remains undetermined, as pre-mRNA splicing is unaffected in patients. We generated human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1 and show that this mutation impairs human hematopoiesis. Dysregulated microRNA (miRNA) levels in USB1 mutants during blood development contribute to hematopoietic failure, because of a failure to remove 3′-end adenylated tails added by PAPD5/7. Modulation of miRNA 3′-end adenylation through genetic or chemical inhibition of PAPD5/7 rescues hematopoiesis in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN.
DOI: abj8379
Source: https://www.science.org/doi/10.1126/science.abj8379