The interplay of the translocase activity and protein recruitment function of PICH in ultrafine anaphase bridge resolution and genomic stability

IF 16.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nucleic Acids Research Pub Date : 2024-12-20 DOI:10.1093/nar/gkae1249

Nannan Kong, Kun Chen, Primrose Chanboonyasitt, Huadong Jiang, Ka Yan Wong, Hoi Tang Ma, Ying Wai Chan

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引用次数: 0

Abstract

Incomplete sister centromere decatenation results in centromeric ultrafine anaphase bridges (UFBs). PICH (PLK1-interacting checkpoint helicase), a DNA translocase, plays a crucial role in UFB resolution by recruiting UFB-binding proteins and stimulating topoisomerase IIα. However, the involvement of distinct PICH functions in UFB resolution remains ambiguous. Here, we demonstrate that PICH depletion in non-transformed diploid cells induces DNA damage, micronuclei formation, p53 activation, G1-phase delay and cell death. Whole-genome sequencing reveals that segregation defects induced by PICH depletion cause chromosomal rearrangements, including translocations and inversions, emphasizing its significance in preserving genomic integrity. Furthermore, a PICH mutant that impairs UFB recruitment of BLM and RIF1 partially inhibits UFB resolution while a translocase-inactive mutant (PICHK128A) fails to resolve UFBs. Notably, expression of PICHK128A inhibits single-stranded UFB formation and induces hypocondensed chromosomes. We propose that PICH’s translocase activity plays a dual role in promoting UFB resolution by facilitating the generation of single-stranded UFBs and stimulating topoisomerase IIα.

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PICH转座酶活性和蛋白质募集功能在超细后期桥分辨率和基因组稳定性中的相互作用

不完全的姐妹中心粒分解会导致中心粒超细无丝分裂桥（UFB）。PICH（PLK1-interacting checkpoint helicase）是一种DNA易位酶，通过招募UFB结合蛋白和刺激拓扑异构酶IIα，在UFB消解过程中发挥着至关重要的作用。然而，PICH在UFB解析中的不同功能仍不明确。在这里，我们证明了在未转化的二倍体细胞中消耗 PICH 会诱导 DNA 损伤、微核形成、p53 激活、G1 期延迟和细胞死亡。全基因组测序显示，PICH耗竭诱导的分离缺陷会导致染色体重排，包括易位和倒位，这强调了它在保持基因组完整性方面的重要性。此外，PICH突变体会损害UFB对BLM和RIF1的招募，从而部分抑制UFB的解析，而易位酶不活跃的突变体（PICHK128A）则不能解析UFB。值得注意的是，PICHK128A 的表达抑制了单链 UFB 的形成，并诱导了染色体的低缩。我们认为，PICH的转位酶活性在促进UFB解析过程中扮演着双重角色，既能促进单链UFB的生成，又能刺激拓扑异构酶IIα。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nucleic Acids Research 生物-生化与分子生物学

CiteScore

27.10

自引率

4.70%

发文量

1057

审稿时长

2 months

期刊介绍： Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.