DNA damage responses in murine Pre-B cells with genetic deficiencies in damage response genes

被引:7
作者
Innes, Cynthia L. [1 ,4 ]
Hesse, Jill E. [1 ,5 ]
Morales, Abigail J. [2 ,6 ]
Helmink, Beth A. [2 ,7 ]
Schurman, Shepherd H. [3 ]
Sleckman, Barry P. [2 ,8 ]
Paules, Richard S. [1 ,9 ]
机构
[1] NIEHS, Environm Stress & Canc Grp, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA
[2] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA
[3] NIEHS, Clin Res Branch, Div Intramural Res, Durham, NC USA
[4] NIEHS, Clin Res Branch, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA
[5] Q2 Solut, 5927 S Miami Blvd 100, Morrisville, NC USA
[6] CUNY, Hunter Coll, Dept Med Lab Sci, New York, NY 10021 USA
[7] MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX USA
[8] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA
[9] NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA
关键词
B cells; ionizing radiation; DNA damage; double strand breaks; transcriptome profiles; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; CYCLE CHECKPOINT; ATM ACTIVATION; MRE11; COMPLEX; MRN COMPLEX; RHO-GTPASES; P53; REPAIR; PROTEIN;
D O I
10.1080/15384101.2019.1693118
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
DNA damage can be generated in multiple ways from genotoxic and physiologic sources. Genotoxic damage is known to disrupt cellular functions and is lethal if not repaired properly. We compare the transcriptional programs activated in response to genotoxic DNA damage induced by ionizing radiation (IR) in abl pre-B cells from mice deficient in DNA damage response (DDR) genes Atm, Mre11, Mdc1, H2ax, 53bp1, and DNA-PKcs. We identified a core IR-specific transcriptional response that occurs in abl pre-B cells from WT mice and compared the response of the other genotypes to the WT response. We also identified genotype specific responses and compared those to each other. The WT response includes many processes involved in lymphocyte development and immune response, as well as responses associated with the molecular mechanisms of cancer, such as TP53 signaling. As expected, there is a range of similarity in transcriptional profiles in comparison to WT cells, with Atm-/- cells being the most different from the core WT DDR and Mre11 hypomorph (Mre11(A/A)) cells also very dissimilar to WT and other genotypes. For example, NF-kB-related signaling and CD40 signaling are deficient in both Atm-/- and Mre11(A/A) cells, but present in all other genotypes. In contrast, IR-induced TP53 signaling is seen in the Mre11(A/A) cells, while these responses are not seen in the Atm-/- cells. By examining the similarities and differences in the signaling pathways in response to IR when specific genes are absent, our results further illustrate the contribution of each gene to the DDR. The microarray gene expression data discussed in this paper have been deposited in NCBI's Gene Expression Omnibus (GEO) () and are accessible under accession number GSE116388.
引用
收藏
页码:67 / 83
页数:17
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