HP1 regulates the localization of FANCJ at sites of <scp>DNA</scp> double‐strand breaks

Wu, Wenwen; Togashi, Yukiko; Johmura, Yoshikazu; Miyoshi, Yasuo; Nobuoka, Sachihiko; Nakanishi, Makoto; Ohta, Tomohiko

doi:10.1111/cas.13008

Cited by 13 publications

(12 citation statements)

References 63 publications

(181 reference statements)

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“…These findings suggest that the tandem BRCT domains could contribute, along with the pentapeptide, to the interaction with HP1α. This is reminiscent of what observed in BARD1 in which the conserved HP1α-binding pentapeptide is located within the BRCT domain and allows the interaction with the CSD of HP1α 56,57 . Differently from NBS1 silencing, the interaction of p26- and p70-NBS1 fragments with HP1α results in an accumulation of HP1α through mechanisms that remain unclear.…”

Section: Discussionmentioning

confidence: 60%

NBS1 interacts with HP1 to ensure genome integrity

et al. 2019

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Heterochromatin Protein 1 (HP1) and the Mre11-Rad50-Nbs1 (MRN) complex are conserved factors that play crucial role in genome stability and integrity. Despite their involvement in overlapping cellular functions, ranging from chromatin organization, telomere maintenance to DNA replication and repair, a tight functional relationship between HP1 and the MRN complex has never been elucidated. Here we show that the Drosophila HP1a protein binds to the MRN complex through its chromoshadow domain (CSD). In addition, loss of any of the MRN members reduces HP1a levels indicating that the MRN complex acts as regulator of HP1a stability. Moreover, overexpression of HP1a in nbs (but not in rad50 or mre11) mutant cells drastically reduces DNA damage associated with the loss of Nbs suggesting that HP1a and Nbs work in concert to maintain chromosome integrity in flies. We have also found that human HP1α and NBS1 interact with each other and that, similarly to Drosophila, siRNA-mediated inhibition of NBS1 reduces HP1α levels in human cultured cells. Surprisingly, fibroblasts from Nijmegen Breakage Syndrome (NBS) patients, carrying the 657del5 hypomorphic mutation in NBS1 and expressing the p26 and p70 NBS1 fragments, accumulate HP1α indicating that, differently from NBS1 knockout cells, the presence of truncated NBS1 extends HP1α turnover and/or promotes its stability. Remarkably, an siRNA-mediated reduction of HP1α in NBS fibroblasts decreases the hypersensitivity to irradiation, a characteristic of the NBS syndrome. Overall, our data provide an unanticipated evidence of a close interaction between HP1 and NBS1 that is essential for genome stability and point up HP1α as a potential target to counteract chromosome instability in NBS patient cells.

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Section: Discussionmentioning

confidence: 60%

NBS1 interacts with HP1 to ensure genome integrity

et al. 2019

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“…The BRCT domain has been shown to interact with the HP1 protein in order to retain both the BRCA1-BARD1 complex and CtIP, which is involved in DNA end resection, at the damage site [26]. The BARD1-HP1 interaction is also necessary for the accumulation of DNA helicase FANCJ at sites of DNA damage [37]. BARD1 L570E/V571E and L570A/V571A variants have been shown to inhibit the interaction between BARD1 and HP1 [26].…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity

et al. 2019

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The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.

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“…Not only this, but YM-155 also adversely affects the partner and localizer of BRCA2 (PALB2 [-2.33, p<0.001]), which is required for protein linking BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break. This is pivotal because a combined reduction of BRCA1 interacting protein C-terminal helicase 1, BRIP1 [-6.37, p=6.43E-07] (FANCJ) at both time points would prevent its role as a major helicase needed to interact with BRCA1 to oversee homologous recombination DNA repair and cell response to replication stresses (64). Although many more targets are centered around YM-155 mediated impairment to the DNA damage response pathway, as a last example, we see reduction in exonuclease 1 (EXO1 [-4.57, p<0.001]) which is required for 5' resection in DNA mismatch repair processes involving homologous recombination repair at stalled replication forks (65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

Mazzio

Lewis

Elhag

et al. 2018

Cancer Genomics Proteomics

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Sepantronium bromide (YM-155) is believed to elicit apoptosis and mitotic arrest in tumor cells by reducing (BIRC5, survivin) mRNA. In this study, we monitored changes in survivin mRNA and protein after treating MDA-MB-231 cells with YM-155 concurrent with evaluation of whole transcriptomic (WT) mRNA and long intergenic non-coding RNA at 2 time points: 8 h sub-lethal (83 ng/mL) and 20 h at the LC (14.6 ng/mL). The data show a tight association between cell death and the precipitating loss of survivin protein and mRNA (-2.67 fold-change (FC), p<0.001) at 20 h, questioning if the decline in survivin is attributed to cell death or drug impact. The meager loss of survivin mRNA was overshadowed by enormous differential change to the WT in both magnitude and significance for over 2000 differentially up/down-regulated transcripts: (+22 FC to -12 FC, p<0.001). The data show YM-155 to up-regulate transcripts in control of circadian rhythm (NOCT, PER, BHLHe40, NFIL3), tumor suppression (SIK1, FOSB), histone methylation (KDM6B) and negative feedback of NF-kappa B signaling (TNFAIP3). Down-regulated transcripts by YM-155 include glucuronidase (GUSBP3), numerous micro-RNAs, DNA damage repair elements (CENPI, POLQ, RAD54B) and the most affected system was the ataxia-telangiectasia mutated (ATM)/Fanconi anemia E3 monoubiquitin ligase core complexes (FANC transcripts - A/B/E/F/G/M), FANC2, FANCI, BRCA1, BRCA2, RAD51, PALB2 gene and ATR (ATM- and Rad3-Related) pathway. In conclusion, these findings suggest that a primary target of YM-155 is the loss of replicative DNA repair systems.

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HP1 regulates the localization of FANCJ at sites of DNA double‐strand breaks

Cited by 13 publications

References 63 publications

NBS1 interacts with HP1 to ensure genome integrity

NBS1 interacts with HP1 to ensure genome integrity

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

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