FIRRM/C1orf112 与 PICH 具有合成致死性，并介导 RAD51 动力学。

FIRRM/C1orf112 is synthetic lethal with PICH and mediates RAD51 dynamics.

机构信息

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.

Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany.

出版信息

Cell Rep. 2023 Jul 25;42(7):112668. doi: 10.1016/j.celrep.2023.112668. Epub 2023 Jun 21.

DOI:10.1016/j.celrep.2023.112668

PMID:37347663

Abstract

Joint DNA molecules are natural byproducts of DNA replication and repair. Persistent joint molecules give rise to ultrafine DNA bridges (UFBs) in mitosis, compromising sister chromatid separation. The DNA translocase PICH (ERCC6L) has a central role in UFB resolution. A genome-wide loss-of-function screen is performed to identify the genetic context of PICH dependency. In addition to genes involved in DNA condensation, centromere stability, and DNA-damage repair, we identify FIGNL1-interacting regulator of recombination and mitosis (FIRRM), formerly known as C1orf112. We find that FIRRM interacts with and stabilizes the AAA ATPase FIGNL1. Inactivation of either FIRRM or FIGNL1 results in UFB formation, prolonged accumulation of RAD51 at nuclear foci, and impaired replication fork dynamics and consequently impairs genome maintenance. Combined, our data suggest that inactivation of FIRRM and FIGNL1 dysregulates RAD51 dynamics at replication forks, resulting in persistent DNA lesions and a dependency on PICH to preserve cell viability.

摘要

连接 DNA 分子是 DNA 复制和修复的自然副产物。持续存在的连接分子会在有丝分裂中产生超微 DNA 桥（UFB），从而影响姐妹染色单体的分离。DNA 易位酶 PICH（ERCC6L）在 UFB 解析中起着核心作用。进行全基因组功能丧失筛选，以确定 PICH 依赖性的遗传背景。除了参与 DNA 浓缩、着丝粒稳定性和 DNA 损伤修复的基因外，我们还鉴定了与 FIGNL1 相互作用的重组和有丝分裂调节剂（FIRRM），以前称为 C1orf112。我们发现 FIRRM 与 AAA ATP 酶 FIGNL1 相互作用并稳定其结构。无论是 FIRRM 还是 FIGNL1 的失活都会导致 UFB 的形成、RAD51 在核斑点中的持续积累以及复制叉动力学的受损，从而损害基因组的维持。综上所述，我们的数据表明，FIRRM 和 FIGNL1 的失活会使 RAD51 在复制叉处的动力学失调，导致持续的 DNA 损伤，并依赖 PICH 来维持细胞活力。