BCR/ABL kinase interacts with and phosphorylates the RAD51 paralog, RAD51B

Słupianek, Artur; Jóźwiakowski, Stanisław K.; Gurdek, Ewa; Skórski, Tomasz

doi:10.1038/leu.2009.164

Cited by 10 publications

(4 citation statements)

References 7 publications

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“…The latter two were also induced by ROMI and thus not specific to VPA activity. Of the remaining five genes (ABL1, BARD1, MAPK12, MPG, and RAD51), BARD1 and RAD51 directly function as part of HR-mediated repair, while ABL1-mediated phosphorylation of RAD51 can regulate RAD51 function (23,24). It is interesting to note that RAD51 was identified in a set of 13 genes whose loss of expression synergized with PARPi, validating our experiment (25)(26)(27).…”

Section: Hdac Inhibitors Suppress Hr Activity In Breast Cancer Cells supporting

confidence: 55%

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

Wiegmans

Yap

Ward

et al. 2015

Molecular Cancer Therapeutics

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The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2-specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting.

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Section: Hdac Inhibitors Suppress Hr Activity In Breast Cancer Cells supporting

confidence: 55%

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

Wiegmans

Yap

Ward

et al. 2015

Molecular Cancer Therapeutics

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“…In BCR-ABL-expressing cells, levels of DNA-PK were down-regulated, which may interfere with non-homologous end joining activity [49]. BCR-ABL also interferes with the Fanconi anemia/BRCA pathway [50,51], or enhances the expression/activity of RAD51, and may induce genomic instability [52,53]. Thus, BCR-ABL is a direct inhibitor of genomic stability.…”

Section: Dna Damage Response Work As a Cancerous Progression Barriermentioning

confidence: 99%

DNA damage response and hematological malignancy

Takagi

2017

Int J Hematol

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errors. The metabolites, reactive oxygen species, reactive nitrogen species, reactive carbonyl species, lipid peroxidation products affect DNA integrity. Other than these metabolites, V(D)J recombination process mediated by RAG1/2 during lymphocyte development involves DNA double-strand breaks (DSB). DNA topoisomerase 2 also induces DSB to control DNA topologic status. Deamination induced by deaminases or depurination leads to DNA single-strand breaks (SSB). SSBs can also arise by DNA topoisomerase 1. Tens of thousands of SSBs, 10-50 DSBs per cell per day occur naturally [1][2][3]. ATM is a key regulator of DNA damage check pointOnce cells suffer DNA damage, cells try to resolve damages. The cellular response to DNA damage induces cell cycle arrest, damaged DNA repair, or apoptosis. This machinery is called DNA damage response (DDR), or DNA damage checkpoint. Numerous factors are involved in this process. The central player in DNA damage response, especially in DSB, is ATM. DNA damage response comprised several steps, sensor, transducer, and effector. When DNA DSB happen, the sensor, MRE11-RAD50-NBN (MRN) complex, is recruited to the DSB site [4]. ATM is present as a dimer or higher order multimer in unstressed cell with the kinase domain bound to a region surrounding Ser 1981 that is contained within the FAT domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine-1981 and this phosphorylation event results in dimer dissociation and initiation of cellular ATM kinase activity [5]. Then activated ATM recruited DSB site. Activated ATM transduces the signal to downstream effectors by phosphorylating Abstract DNA damage is a serious threat to cellular homeostasis. Damaged DNA leads to genomic instability, mutation, senescence, and/or cell death. DNA damage triggers a cellular response called the DNA damage response (DDR), followed by activation of the DNA repair machinery. DDR both maintains cellular homeostasis and prevents cancer development. Germ line mutation of DDRassociated genes can lead to cancer-susceptible syndromes. Somatic mutation of DDR-associated genes has also been reported in various tumors, including hematological malignancies. Therapeutic approaches that target the DDR and DNA repair are thus now being developed. Understanding the mechanism(s) underlying DDR and DNA repair will increase our knowledge of cancer etiology and facilitate development of cancer therapies.

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“…Therefore, it seems that BCR-ABL acquires more mutations than non-transformed cells because there is greater DNA damage and more enhanced yet less faithful DNA repair. Altogether, BCR-ABL kinase chronically activates survival pathways (RAS, PI3K, and STAT) [92], stimulates ROS production that enhances signaling and causes DNA damage in CML cells [160,182,185,186] and alters DNA repair mechanisms [160,[174][175][176][177][187][188][189][190][191] resulting in genomic instability responsible for mutation associated with drug resistance and disease progression.…”

Section: -Oxoguanine (8-oxog) and Base Excision Repair (Ber)mentioning

confidence: 99%

Genomic Instability Originates From Leukemia Stem Cells in a Mouse Model of CML-CP

Bolton

Schemionek

Klein³

et al. 2011

Blood

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445 For decades, chronic myeloid leukemia (CML) has served not only as a paradigm for understanding the evolution and multi-step process of carcinogenesis but also for studying cancer stem and progenitor cells responsible for the initiation and/or maintenance of the disease. CML is initiated by BCR-ABL1 tyrosine kinase transformation of hematopoietic stem cells into leukemia stem cells (LSCs) to induce CML-chronic phase (CML-CP). The deregulated growth of LSC-derived leukemia progenitor cells (LPCs) leads to manifestation of the disease. It is unclear if LSCs and/or LPCs are able to acquire additional genetic changes that confer resistance to tyrosine kinase inhibitors (TKIs) and induce more aggressive CML blast phase (CML-BP). In addition, the mechanisms and consequences of genomic instability may differ substantially among these cells. For example, the effects of genetic aberrations acquired in quiescent LSCs may be dormant, but if the aberrations induce proliferation or appear in LSCs that are already cycling, they may generate TKI-resistant and/or more malignant clones. Alternatively, genomic instability in LPCs must be accompanied by the acquisition of LSC-like properties to prevent mutations from disappearing before they undergo terminal maturation. Previously, we reported that BCR-ABL1–transformed cell lines accumulate reactive oxygen species (ROS)-induced oxidative DNA damage [8-oxoguanine (8oxoG), double strand breaks (DSBs)] resulting in genomic instability in vitro, which was responsible for acquired imatinib-resistance and accumulation of chromosomal aberrations (Nowicki et al., Blood, 2005; Koptyra et al., Blood, 2006; Koptyra et al., Leukemia, 2008). To determine which populations of CML-CP cells, LSCs and/or LPCs, accumulate genomic instability we employed the SCLtTA/BCR-ABL1 tetracycline-inducible (tet-off) transgenic mouse model of CML-CP with targeted expression of p210BCR-ABL1 in hematopoietic stem and progenitor cells (Koschmieder et al., Blood, 2005). Mice exhibiting CML-CP-like disease resulting from BCR-ABL1 induction demonstrated splenomegaly and Gr1+/CD11b+ myeloid expansion in bone marrow, spleen and peripheral blood. BCR-ABL1 mRNA expression was higher in the Lin−c-Kit+Sca1+ murine leukemia stem cell–enriched population (muLSCs) than in the Lin−c-Kit+Sca1− murine leukemia progenitor cell–enriched population (muLPCs), thus reminiscent of human CML-CP (Lin−CD34+CD38− LSCs > Lin−CD34+CD38+ LPCs). BCR-ABL1 induction increased levels of ROS (hydrogen peroxide, hydroxyl radical) and oxidative DNA damage (8-oxoG, DSBs) in muLSCs, but not in muLPCs. In addition, CFSEmax/eFluor670max quiescent muLSCs displayed more ROS (superoxide, hydrogen peroxide) and oxidative DNA damage (8oxoG, DSBs) than non-induced counterparts. Currently, we are examining genomic instability in the most primitive long-term muLSCs (Lin−c-Kit+Sca1+CD34−Flt3−). Lastly, single nucleotide polymorphism (SNP) arrays detected a variety of genetic aberrations (addition, deletions) in BCR-ABL1–induced Lin− BM cells. Individual mice displayed a great degree of diversity in the intensity of genetic instability accumulating between 31 to 826 aberrations, which recapitulate heterogeneity of sporadic aberrations detected in CML-CP patients. These aberrations include deletions in Trp53 and Ikzf1, and additions in Zfp423 and Idh1 genes, which have been linked to progression from CML-CP to CML-BP. In summary, by using the SCLtTA/BCR-ABL1 inducible transgenic mouse model of CML-CP we showed that muLSCs, but not muLPCs, displayed elevated levels of ROS-induced oxidative DNA damage likely resulting in the accumulation of extensive genetic aberrations. This observation supports the hypothesis that genomic instability in CML-CP originates in LSCs. Current analysis of microarrays may shed some light on the mechanisms leading to enhanced ROS production and accumulation of oxidative DNA damage in muLSCs. Disclosures: Koschmieder: Novartis, Bristol-Myers Squibb: Consultancy.

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BCR/ABL kinase interacts with and phosphorylates the RAD51 paralog, RAD51B

Cited by 10 publications

References 7 publications

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

DNA damage response and hematological malignancy

Genomic Instability Originates From Leukemia Stem Cells in a Mouse Model of CML-CP

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