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同源重组在DNA损伤时促进非免疫原性有丝分裂细胞死亡。

Homologous recombination promotes non-immunogenic mitotic cell death upon DNA damage.

作者信息

Szmyd Radoslaw, Casolin Sienna, French Lucy, Manjón Anna G, Walter Melanie, Cavalli Léa, Nelson Christopher B, Page Scott G, Dhawan Andrew, Hau Eric, Pickett Hilda A, Gee Harriet E, Cesare Anthony J

机构信息

Genome Integrity Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia.

Radiation Oncology Network, Western Sydney Local Health District, Sydney, New South Wales, Australia.

出版信息

Nat Cell Biol. 2025 Jan;27(1):59-72. doi: 10.1038/s41556-024-01557-x. Epub 2025 Jan 13.

DOI:10.1038/s41556-024-01557-x
PMID:39805921
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11735404/
Abstract

Double-strand breaks (DSBs) can initiate mitotic catastrophe, a complex oncosuppressive phenomenon characterized by cell death during or after cell division. Here we unveil how cell cycle-regulated DSB repair guides disparate cell death outcomes through single-cell analysis of extended live imaging. Following DSB induction in S or G2, passage of unresolved homologous recombination intermediates into mitosis promotes non-immunogenic intrinsic apoptosis in the immediate attempt at cell division. Conversely, non-homologous end joining, microhomology-mediated end joining and single-strand annealing cooperate to enable damaged G1 cells to complete the first cell cycle with an aberrant cell division at the cost of delayed extrinsic lethality and interferon production. Targeting non-homologous end joining, microhomology-mediated end joining or single-strand annealing promotes mitotic death, while suppressing mitotic death enhances interferon production. Together the data indicate that a temporal repair hierarchy, coupled with cumulative DSB load, serves as a reliable predictor of mitotic catastrophe outcomes following genome damage. In this pathway, homologous recombination suppresses interferon production by promoting mitotic lethality.

摘要

双链断裂（DSB）可引发有丝分裂灾难，这是一种复杂的肿瘤抑制现象，其特征是在细胞分裂期间或之后发生细胞死亡。在此，我们通过对长时间活细胞成像的单细胞分析，揭示了细胞周期调控的DSB修复如何引导不同的细胞死亡结果。在S期或G2期诱导DSB后，未解决的同源重组中间体进入有丝分裂会在细胞立即尝试分裂时促进非免疫原性的内源性凋亡。相反，非同源末端连接、微同源性介导的末端连接和单链退火协同作用，使受损的G1期细胞能够以延迟的外源性致死率和干扰素产生为代价，通过异常的细胞分裂完成第一个细胞周期。靶向非同源末端连接、微同源性介导的末端连接或单链退火可促进有丝分裂死亡，而抑制有丝分裂死亡则会增强干扰素的产生。这些数据共同表明，一个时间修复层次结构，加上累积的DSB负荷，可作为基因组损伤后有丝分裂灾难结果的可靠预测指标。在这条通路中，同源重组通过促进有丝分裂致死性来抑制干扰素的产生。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/8965a23c4071/41556_2024_1557_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/895c45577a2e/41556_2024_1557_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/7209670a1c64/41556_2024_1557_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/b3e2c041f698/41556_2024_1557_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/5cc15a84a433/41556_2024_1557_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/8408ece0f0e3/41556_2024_1557_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c880/11735404/bfc8bacadbfe/41556_2024_1557_Fig15_ESM.jpg
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引用本文的文献

[1]
DNA-repair-driven cell death compels us to rethink cancer therapies.

Nat Rev Mol Cell Biol. 2025-8-1

[2]
A CPC-shelterin-BTR axis regulates mitotic telomere deprotection.

Nat Commun. 2025-3-17

[3]
Roles for the 3D genome in the cell cycle, DNA replication, and double strand break repair.

Front Cell Dev Biol. 2025-2-27

[4]
Mitotic lethality prevents inflammation.

Nat Cell Biol. 2025-1

本文引用的文献

[1]
Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis.

Nature. 2023-9

[2]
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[3]
RHINO directs MMEJ to repair DNA breaks in mitosis.

Science. 2023-8-11

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POLQ inhibition elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma via cGAS/STING signaling.

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Signal Transduct Target Ther. 2021-11-26

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Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells.

Proc Natl Acad Sci U S A. 2021-11-30

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Nat Cell Biol. 2021-10

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Nat Rev Mol Cell Biol. 2022-2

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Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

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