Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model

Balestrini, Alessia; Nicolás, Laura; Yang-lott, Katherine; Guryanova, Olga A.; Levine, Ross L.; Bassing, Craig H.; Chaudhuri, Jayanta; Petrini, John H.J.

doi:10.1158/1541-7786.mcr-15-0281

Cited by 10 publications

(17 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas pro-B cells (CD43 + ) from Nbs1 -/mid8vav were increased ( Figure 2E), the levels of B220 + cells decreased beginning at the pre B stage when immunoglobulin heavy chain rearrangement commences (Alt et al, 2013;Teng and Schatz, 2015) to the immature B cell stage (CD43 -), and IgM + mature B cells were virtually undetectable ( Figure 2F-H). These data suggest that Nbs1 -/mid8vav cells are unable to resolve DSBs formed during the course of B cell development, reminiscent of previous analyses of lymphocyte development in Mre11 complex mutants (Balestrini et al, 2016;Callen et al, 2007;Deriano et al, 2009;Helmink et al, 2009). The hematopoietic phenotype of Nbs1 -/mid8vav mice is distinct from that of Atm -/-vav in all respects ( Figure 1E…”

Section: Nbs1 -/Mid8vav and Hematopoiesissupporting

confidence: 64%

See 1 more Smart Citation

Nbs1 Mediates Assembly and Activity of the Mre11 complex

Kim

Penson

Taylor

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

We derived a mouse model in which a mutant form of Nbs1 (Nbs1 mid8 ) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbs1 mid8 allele was expressed exclusively in hematopoietic lineages (in Nbs1 -/mid8vav mice). Unlike Nbs1 flox/floxvav mice, which are Nbs1 deficient in the bone marrow, Nbs1 -/mid8vav mice were viable. Nbs1 -/mid8vav hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage specific blockage of B cell development. Within six months, Nbs1 -/mid8 mice developed highly penetrant T cell leukemias. Nbs1 -/mid8vav leukemias recapitulated mutational features of human T-ALL, containing mutations in Notch1, Trp53, Bcl6, Bcor, and Ikzf1, suggesting that Nbs1 mid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbs1 -/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1. We propose that overexpression compensates for the meta-stable Mre11-Nbs1 mid8 interaction, and that selection pressure for overexpression reflects the essential role of Nbs1 in promoting assembly and activity of the Mre11 complex.Ddx3x

show abstract

Section: Nbs1 -/Mid8vav and Hematopoiesissupporting

confidence: 64%

“…The Mre11 complex is required for hematopoiesis (Adelman et al, 2009;Balestrini et al, 2016;Callen et al, 2007;Reina-San-Martin et al, 2005). We asked whether the Nbs1 mid8 gene product had sufficient residual function to allow hematopoietic stem cells expressing only Nbs1 mid8 to support hematopoietic development.…”

Section: Nbs1 -/Mid8vav and Hematopoiesismentioning

confidence: 99%

Nbs1 Mediates Assembly and Activity of the Mre11 complex

Kim

Penson

Taylor

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…To determine whether the rescue fragments would sustain viability in vivo , we assessed their ability to support the differentiation of lymphocytes. Previous analyses indicated that the Mre11 complex is required for lymphocyte development (Balestrini et al, 2015; Callen et al, 2007; Deriano et al, 2009; Reina-San-Martin et al, 2004). Nbs1 F/F mice were crossed to vavCre mice, which express cre recombinase in hematopoietic stem cells (HSCs) (Stadtfeld and Graf, 2005).…”

Section: Resultsmentioning

confidence: 99%

The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression

et al. 2017

Self Cite

View full text Add to dashboard Cite

SUMMARY The Mre11 complex (Mre11, Rad50 and Nbs1) is integral to both DNA repair and ATM-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal level. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1mid mice) which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1mid alleles that abolished interaction were incompatible with viability. Conversely, a 108 amino acid Nbs1 fragment comprising the Mre11 interface was sufficient to rescue viability and ATM activation in cultured cells and to support differentiation of hematopoietic cells in vivo. These data indicate that the essential role of Nbs1 is via its interaction with Mre11, that most of the Nbs1 protein is dispensable for Mre11 complex functions, and suggest that Mre11 and Rad50 directly activate ATM.

show abstract

“…The MRN complex is a multifunctional enzyme conglomerate known to activate cell cycle checkpoints when sensing DNA breakage (Stracker and Petrini, 2011). In addition to a critical role in ATM function and double strand break repair, MRN is also implicated in suppression of lymphomagenesis (Balestrini et al, 2015) and regulating metastatic breast cancers (Gupta et al, 2013). In humans, MRE11A mutations cause an ataxia-telangiectasia-like disease, with considerable variability in clinical phenotypes (Taylor et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis

Shen

Hohensinner

et al. 2016

Immunity

View full text Add to dashboard Cite

Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4+ T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, pro-inflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11Alow T cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.

show abstract

Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model

Cited by 10 publications

References 50 publications

Nbs1 Mediates Assembly and Activity of the Mre11 complex

Nbs1 Mediates Assembly and Activity of the Mre11 complex

The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression

Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis

Contact Info

Product

Resources

About