RADIF(C1orf112)-FIGNL1 Complex Regulates RAD51 Chromatin Association to Promote Viability After Replication Stress.
RADIF(C1orf112)-FIGNL1 Complex Regulates RAD51 Chromatin Association to Promote Viability After Replication Stress.
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RADIF(C1orf112)-FIGNL1 复合物调节 RAD51 染色质关联以促进复制应激后的活力。
DOI：
10.1101/2023.09.25.556595
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Adeyemi,RichardO
中科院分区：
文献类型：
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作者：
Tischler,JessicaD;Tsuchida,Hiroshi;Oda,TommyT;Park,Ana;Adeyemi,RichardO
同源重组 (HR) 在修复 DNA 复制过程中出现的损伤中发挥着关键作用，因此对于生存至关重要。 RAD51在复制和同源重组过程中发挥重要作用，然而，RAD51如何在核丝形成下游受到调节以及如何调节RAD51的各种功能尚不清楚。我们研究了蛋白质 c1orf112/FLIP，该蛋白质先前在 DNA 链间交联 (ICL) 修复介体的全基因组筛选中得分。暴露于 ICL 试剂后，FLIP 丢失会导致显着的细胞死亡、染色体不稳定性增加、微核形成增加、细胞周期进程改变和 DNA 损伤信号传导增加。 FLIP 被招募来损伤病灶并与FigNL1 形成复合物。两种蛋白在 ICL 修复中都具有上位作用，形成稳定的复合物。从机制上讲，FLIP 丢失会导致 RAD51 数量增加并集中在染色质上，无论有或没有外源 DNA 损伤、复制叉进展缺陷和 HR 能力降低。我们假设 FLIP 对于在没有损伤的情况下限制染色质上的 RAD51 水平以及 RAD51 从核丝解离以正确完成 HR 至关重要。如果不这样做会导致复制速度减慢并且无法完成修复。
Homologous recombination (HR) plays critical roles in repairing lesions that arise during DNA replication and is thus essential for viability. RAD51 plays important roles during replication and HR, however, how RAD51 is regulated downstream of nucleofilament formation and how the varied RAD51 functions are regulated is not clear. We have investigated the protein c1orf112/FLIP that previously scored in genome-wide screens for mediators of DNA inter-strand crosslink (ICL) repair. Upon ICL agent exposure, FLIP loss leads to marked cell death, elevated chromosomal instability, increased micronuclei formation, altered cell cycle progression and increased DNA damage signaling. FLIP is recruited to damage foci and forms a complex with FIGNL1. Both proteins have epistatic roles in ICL repair, forming a stable complex. Mechanistically, FLIP loss leads to increased RAD51 amounts and foci on chromatin both with or without exogenous DNA damage, defective replication fork progression and reduced HR competency. We posit that FLIP is essential for limiting RAD51 levels on chromatin in the absence of damage and for RAD51 dissociation from nucleofilaments to properly complete HR. Failure to do so leads to replication slowing and inability to complete repair.