Interplay with the Mre11-Rad50-Nbs1 complex and phosphorylation by GSK3β implicate human B-Myb in DNA-damage signaling

Henrich, Sarah Marie; Usadel, Clemens; Werwein, Eugen; Burdová, Kamila; Janscak, Pavel; Ferrari, Stefano; Heß, Daniel; Klempnauer, Karl‐Heinz

doi:10.1038/srep41663

Cited by 14 publications

(25 citation statements)

References 48 publications

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“…In agreement with our conclusions, studies using human cell lines have recently demonstrated that MYBL2 interacts with Nbs1, which is required for the activation of ATM in response to DSBs and also ATM-dependent heterochromatic DSB repair in G 0 -G 1 (9). While on face value, this may explain our observations Mybl2 þ/D HSCs, in stark contrast to the work of Henrich and colleagues, we were unable to detect a G 2 -M checkpoint defect in our Mybl2-haploinsufficient HSCs, suggesting that at least some ATM-dependent signaling is intact in these cells.…”

Section: Discussionsupporting

confidence: 93%

“…Genetic alterations are often present in MDS and a frequent chromosome abnormality is del20q, whose common deleted region only contains 5 genes expressed in HSCs, one of which is MYBL2 (2,3). The MYBL2 gene encodes a ubiquitously expressed protein belonging to the MYB family of transcription factors and has been shown to form part of different protein complexes such as the Myb-MuvB/DREAM complex (4-7), Myb-Clafi complex (8), and the MRN complex (9), through which it exerts its vital role in cell-cycle regulation and maintenance of genome stability (10)(11)(12)(13)(14). Analysis of publicly available global gene expression data from CD34 þ -MDS patient cells (15) have confirmed that downregulation of MYBL2 expression correlates with poor prognosis; even in patients with a normal karyotype (2,3).…”

Section: Introductionmentioning

confidence: 99%

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MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

et al. 2018

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Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by blood cytopenias that occur as a result of somatic mutations in hematopoietic stem cells (HSC). MDS leads to ineffective hematopoiesis, and as many as 30% of patients progress to acute myeloid leukemia (AML). The mechanisms by which mutations accumulate in HSC during aging remain poorly understood. Here we identify a novel role for MYBL2 in DNA double-strand break (DSB) repair in HSC. In patients with MDS, low levels associated with and preceded transcriptional deregulation of DNA repair genes. Stem/progenitor cells from these patients display dysfunctional DSB repair kinetics after exposure to ionizing radiation (IR). Haploinsufficiency of in mice also led to a defect in the repair of DSBs induced by IR in HSC and was characterized by unsustained phosphorylation of the ATM substrate KAP1 and telomere fragility. Our study identifies MYBL2 as a crucial regulator of DSB repair and identifies expression levels as a potential biomarker to predict cellular response to genotoxic treatments in MDS and to identify patients with defects in DNA repair. Such patients with worse prognosis may require a different therapeutic regimen to prevent progression to AML. These findings suggest levels may be used as a biological biomarker to determine the DNA repair capacity of hematopoietic stem cells from patients with MDS and as a clinical biomarker to inform decisions regarding patient selection for treatments that target DNA repair. http://cancerres.aacrjournals.org/content/canres/78/20/5767/F1.large.jpg .

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

et al. 2018

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“…Upon DNA damage, p130 switches from a hyper-to a hypo-phosphorylated form (Mannefeld et al 2009, Quaas et al 2012. In addition, B-MYB is inactivated in response to DNA damage (Mannefeld et al 2009, Klein et al 2015, Henrich et al 2017. In proliferating cells, p130 is hyper-phosphorylated and binds to CDK2, but DNA damage leads to induction p21, which binds to CDK2, which in turn dissociates from p130, leading to hypophosphorylation of p130 (Quaas et al 2012) (Figure 4).…”

Section: Repression Of Cell Cycle Genes In Response To Cell Stress Anmentioning

confidence: 99%

Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes

Fischer

Müller

2017

Critical Reviews in Biochemistry and Molecular Biology

190

250

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The precise timing of cell cycle gene expression is critical for the control of cell proliferation; de-regulation of this timing promotes the formation of cancer and leads to defects during differentiation and development. Entry into and progression through S phase requires expression of genes coding for proteins that function in DNA replication. Expression of a distinct set of genes is essential to pass through mitosis and cytokinesis. Expression of these groups of cell cycle-dependent genes is regulated by the RB pocket protein family, the E2F transcription factor family, and MuvB complexes together with B-MYB and FOXM1. Distinct combinations of these transcription factors promote the transcription of the two major groups of cell cycle genes that are maximally expressed either in S phase (G1/S) or in mitosis (G2/M). In this review, we discuss recent work that has started to uncover the molecular mechanisms controlling the precisely timed expression of these genes at specific cell cycle phases, as well as the repression of the genes when a cell exits the cell cycle.

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“…Other interesting genes, such as Rad50 (BGIBMGA005449), which is associated with DNA repair functions [44][45][46] and the histidine triad protein gene (BGIBMGA011899), which plays roles in transcription, signal transduction and many peripheral and central nervous system diseases [47] are also shown different mRNA transcript level and DNA methylated level upon BmNPV infection (Table 1).…”

Section: Discussionmentioning

confidence: 99%

DNA methylomes and transcriptomes analysis reveal implication of host DNA methylation machinery in BmNPV proliferation in Bombyx mori

Huang

Zhang

et al. 2019

Preprint

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Background Bombyx mori nucleopolyhedrosis virus (BmNPV) is a major pathogen that threatens the sustainability of the sericultural industry. DNA methylation is a widespread gene regulation mode in epigenetics, which plays an important role in host immune response. Until now, little has been known about epigenetic regulation on virus diseases in insects. This study aims to explore the role of DNA methylation in BmNPV proliferation.Results Inhibiting DNA methyltransferase (DNMT) activity of silkworm can suppress BmNPV replication. The integrated analysis of transcriptomes and DNA methylomes in silkworm midguts infected with or without BmNPV showed that both the expression pattern of transcriptome and DNA methylation pattern are changed significantly upon BmNPV infection. A total of 291 differentially methylated genes (DMGs) were observed in BmNPV infected midguts, among which, 126 genes were hypermethylated and 115 genes were hypomethylated. Significant differences in both mRNA transcript level and DNA methylated levels were found in 26 genes. BS-PCR validated the hypermethylation of BGIBMGA014008 , a structural maintenance of chromosomes protein gene in the BmNPV-infected midgut. In addition, DNMT inhibition reduced the expression of inhibitor of apoptosis family genes, iap1 from BmNPV, Bmiap2, BmSurvivin1 and BmSurvivin2 .Conclusion Our results indicate that DNA methylation plays positive roles in BmNPV proliferation and loss of DNMT activity could induce the apoptosis of infected cells to suppress BmNPV proliferation. Our results may provide a new idea and research direction for the molecular mechanism on insect-virus interaction.

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Interplay with the Mre11-Rad50-Nbs1 complex and phosphorylation by GSK3β implicate human B-Myb in DNA-damage signaling

Cited by 14 publications

References 48 publications

MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes

DNA methylomes and transcriptomes analysis reveal implication of host DNA methylation machinery in BmNPV proliferation in Bombyx mori

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