Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

Albers, Eliene; Sbroggiò, Mauro; Pladevall‐Morera, David; Bizard, Anna H.; Avram, Alexandra; González, Patricia; Martín‐González, Javier; Hickson, Ian D.; López-Contreras, Andrés J.

doi:10.1016/j.celrep.2018.08.071

Cited by 29 publications

(40 citation statements)

References 22 publications

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“…Nevertheless, consistent data demonstrates that PICH plays a critical role in chromosome architecture, organization and faithful chromosome segregation [16,32,44,45]. Knocking out PICH causes embryonic lethality in mice and it is proposed to be caused by excessive DNA damage generated during chromosome segregation [46]. Biochemical analyses show that PICH is a DNA translocase that is able to displace triplex DNA molecules and branch migrate a ‘4-way’ junction structure [47].…”

Section: Ultra-fine Dna Bridge-associated Factorsmentioning

confidence: 99%

The Unresolved Problem of DNA Bridging

Fernández-Casañas

Chan

2018

Genes

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Accurate duplication and transmission of identical genetic information into offspring cells lies at the heart of a cell division cycle. During the last stage of cellular division, namely mitosis, the fully replicated DNA molecules are condensed into X-shaped chromosomes, followed by a chromosome separation process called sister chromatid disjunction. This process allows for the equal partition of genetic material into two newly born daughter cells. However, emerging evidence has shown that faithful chromosome segregation is challenged by the presence of persistent DNA intertwining structures generated during DNA replication and repair, which manifest as so-called ultra-fine DNA bridges (UFBs) during anaphase. Undoubtedly, failure to disentangle DNA linkages poses a severe threat to mitosis and genome integrity. This review will summarize the possible causes of DNA bridges, particularly sister DNA inter-linkage structures, in an attempt to explain how they may be processed and how they influence faithful chromosome segregation and the maintenance of genome stability.

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Section: Ultra-fine Dna Bridge-associated Factorsmentioning

confidence: 99%

The Unresolved Problem of DNA Bridging

Fernández-Casañas

Chan

2018

Genes

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“…Excision repair cross-complementation group 6-like (ERCC6L), also named as Polo-like kinase 1-interacting checkpoint “helicase” (PICH), which was identified as an embryonic development related proteins, has been shown to play critical roles in regulating the development of embryonic, brain and other tissues [ 6 – 8 ]. Recently several reports revealed that abnormal ERCC6L expression has been detected in several malignant solid tumors consisting of breast cancer [ 9 ], kidney cancer [ 10 ], and neuroblastoma [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway

Han

Wang

et al. 2020

BMC Cancer

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Background: Excision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively. Methods: Immunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients' clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting. Results: ERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L. Conclusion: These results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.

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“…Due to the smaller presence of mature B and T cells in these mice, we categorize the observed immunodeficient phenotypes as "leaky SCID", which has previously been described in mice lacking other NHEJ factors, such as Ku70 -/- [6], Artemis -/- [3], Lig4 -/-Trp53 -/-, Xrcc4 -/-Trp53 -/- [9,31], Xlf -/-Atm -/- [19] and Xlf -/-Rag2 -/- [23]. It is important to note that inactivation of Trp53 is not always sufficient to rescue embryonic lethality in mice; for example, PLK1interacting checkpoint helicase (PICH)-deficient mice possess developmental defects in the presence or absence of p53 [38]. Moreover, ATR mutants (Seckel syndrome) are not completely rescued from embryonic lethality with the inactivation of Trp53 [39].…”

Section: Discussionmentioning

confidence: 99%

Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI

Castañeda‐Zegarra

Zhang

Alirezaylavasani

et al. 2020

Preprint

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AbstractNon-homologous end joining (NHEJ) is a DNA repair pathway that is required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, core factors Ku70 and Ku80 form a heterodimer called Ku, which recognizes DSBs and promotes recruitment and function of downstream factors PAXX, Mri, DNA-PKcs, Artemis, XLF, XRCC4, and Lig4. Mutations in several known NHEJ genes can result in immunodeficient phenotypes, including severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we demonstrated that deletion of pro-apoptotic factor Trp53 rescues embryonic lethality in mice with combined deficiency of Xlf and Mri. Furthermore, Xlf−/−Mri−/−Trp53+/− mice possessed reduced body weight, severely reduced mature B and T cell counts in the spleen and thymus, and accumulation of progenitor B cells in the bone marrow. Therefore, we conclude that Mri is functionally redundant with XLF during B and T lymphocyte development in vivo, and that Xlf−/−Mri−/−Trp53+/− mice possess a leaky SCID phenotype.

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Loss of PICH Results in Chromosomal Instability, p53 Activation, and Embryonic Lethality

Cited by 29 publications

References 22 publications

The Unresolved Problem of DNA Bridging

The Unresolved Problem of DNA Bridging

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway

Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI

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