Replication Stress Induces ATR/CHK1-Dependent Nonrandom Segregation of Damaged Chromosomes

Xing, Mingzhao; Zhang, Fengjiao; Liao, Hongwei; Chen, Sisi; Che, Luanqing; Wang, Xiaohui; Bao, Zhengqiang; Ji, Fang; Chen, Gaoying; Zhang, Huihui; Wen, Lan; Chen, Zhihua; Liu, Ying; Hickson, Ian D.; Shen, Huahao; Ying, Songmin

doi:10.1016/j.molcel.2020.04.005

Cited by 15 publications

(8 citation statements)

References 55 publications

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“…Interestingly, while scoring DNA damage in G1 cells we noticed that distribution of FANCD2 or γH2AX foci in aneuploid cells was not always symmetric between daughter cells. Thus, we specifically analyzed the pattern of DNA damage inheritance in the aneuploid sample and the euploid control, along with aphidicolin-treated cells where it has been recently shown that DNA damage can be distributed asymmetrically between daughters 45 . Our data indicated that FANCD2 and γH2AX foci were asymmetrically distributed in about 20 and 10% of aneuploid daughter cells, respectively (Fig.…”

Section: Dormant Origin Firing and Midas Protect Aneuploid Cells From...mentioning

confidence: 99%

Short-term molecular consequences of chromosome mis-segregation for genome stability

et al. 2023

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Chromosome instability (CIN) is the most common form of genome instability and is a hallmark of cancer. CIN invariably leads to aneuploidy, a state of karyotype imbalance. Here, we show that aneuploidy can also trigger CIN. We found that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN. This generates a repertoire of genetically diverse cells with structural chromosomal abnormalities that can either continue proliferating or stop dividing. Cycling aneuploid cells display lower karyotype complexity compared to the arrested ones and increased expression of DNA repair signatures. Interestingly, the same signatures are upregulated in highly-proliferative cancer cells, which might enable them to proliferate despite the disadvantage conferred by aneuploidy-induced CIN. Altogether, our study reveals the short-term origins of CIN following aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for aneuploidy occurrence in tumors.

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Section: Dormant Origin Firing and Midas Protect Aneuploid Cells From...mentioning

confidence: 99%

Short-term molecular consequences of chromosome mis-segregation for genome stability

et al. 2023

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“…Interestingly, while scoring DNA damage in G1 cells we noticed that distribution of FANCD2 or ѱH2AX foci in aneuploid cells was not always symmetric between daughter cells. Thus, we decided to specifically look at the pattern of DNA damage inheritance in the aneuploid sample and the euploid control, along with aphidicolin-treated cells where it has been recently shown that DNA damage can be distributed asymmetrically between daughters 51 . Our data indicated that FANCD2 and ѱH2AX foci were asymmetrically distributed in about 20% and 10% of aneuploid daughter cells, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

Short-term molecular consequences of chromosome mis-segregation for genome stability

Feudis

Garribba

Martis

et al. 2022

Preprint

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Genome instability is a hallmark of cancer. The most common form of genome instability is chromosomal instability (CIN), a condition in which cells mis-segregate their chromosomes during cell division. CIN leads to aneuploidy, a state of karyotype imbalance, often found in tumors. Although the causal relationship between CIN and aneuploidy is well established, evidence is limited for a direct involvement of aneuploidy in promoting CIN. Here, we show that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN, eventually accumulating complex karyotypes. Mechanistically, we find that aneuploid cells fire dormant replication origins through a Dbf4-dependent kinase (DDK)-driven mechanism and complete replication of genomic loci through mitotic DNA synthesis (MiDAS). By following the fate of aneuploid cells, we also show that, when they divide, DNA damage can be distributed asymmetrically between daughter cells, and this may partially explain why some aneuploid cells are able to continue proliferating and others stop dividing. We further found that cycling aneuploid cells display lower karyotype complexity compared to arrested ones and increased expression of gene signatures associated to DNA repair. Interestingly, by stratifying aneuploid human cancer cells by their doubling times, we found the same DNA repair signatures to be upregulated in highly-proliferative cancer cells, which might enable them to keep proliferating despite the disadvantage conferred by aneuploidy-induced genome instability. In summary, our study reveals the origins of genome instability following induction of aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for the high occurrence of aneuploidy in tumors.

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“…The ATM/ATR-Chk1 signaling pathway is essential for G2/M arrest following DNA damage ( 36 , 37 ). Therefore, we determined whether these signaling pathways were activated in Ddb1-TaKO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Together these data suggested that loss of Ddb1 in activated CD4 + T cells led to accumulation of DNA damage during acute viral infection. The ATM/ATR-Chk1 signaling pathway is essential for G2/M arrest following DNA damage (36,37). Therefore, we determined whether these signaling pathways were activated in…”

Section: Ddb1 Deficiency Causes Aberrant Dna Damage Responsesmentioning

confidence: 99%

Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Yang

Chen

et al. 2021

Front. Immunol.

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Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4+ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4+ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4+ helper T cells.

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Replication Stress Induces ATR/CHK1-Dependent Nonrandom Segregation of Damaged Chromosomes

Cited by 15 publications

References 55 publications

Short-term molecular consequences of chromosome mis-segregation for genome stability

Short-term molecular consequences of chromosome mis-segregation for genome stability

Short-term molecular consequences of chromosome mis-segregation for genome stability

Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

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