Non-homologous end joining mediated DNA repair is impaired in the NUP98-HOXD13 mouse model for myelodysplastic syndrome

Abstract

Chromosomal translocations typically impair cell differentiation and often require secondary mutations for malignant transformation. However, the role of a primary translocation in the development of collaborating mutations is debatable. To delineate the role of leukemic translocation NUP98-HOXD13 (NHD13) in secondary mutagenesis, DNA break and repair mechanisms in stimulated mouse B lymphocytes expressing NHD13 were analyzed. Our results showed significantly reduced expression of non-homologous end joining (NHEJ)-mediated DNA repair genes, DNA Pkcs, DNA ligase4, and Xrcc4 leading to cell cycle arrest at G2/M phase. Our results showed that expression of NHD13 fusion gene resulted in impaired NHEJ-mediated DNA break repair.

Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1

“…This is in agreement with increased DNA instability in low-risk MDS patients 58,59 and decreased DNA-PK-dependent classical NHEJ repair in a mouse model of MDS. 60 …”

Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?

“…The most direct evidence that DSB misrepair plays a role in MDS is provided by transgenic MDS mouse models [28, 50–52]. Using an in vitro LacZ plasmid end-joining assay, which measures the fidelity of NHEJ by determining the ratio between correctly repaired colonies (which appear white) and incorrectly repaired colonies (blue), it was demonstrated that bone marrow cells from transgenic NRAS or BCL2 mice had increased misrepair frequencies compared to wild-type controls (NRAS versus wild-type: 7.6% and 3.9%, respectively; BCL2 versus wild-type: 6.5% and 3.9%) [51].…”

“…Interestingly, compound NRAS+BCL2 transgenic mice, which develop leukemia in early adulthood, showed an even higher proportion of cells with DNA damage (62%), suggesting that with increasing severity of disease state (from wild-type, via an MDS-like disease, to overt leukemia) the percentage of cells carrying DSBs dramatically increases [51]. Aberrant NHEJ may also be a contributing factor to MDS development in NUP98/HOXD13 transgenic mice; expression levels of important NHEJ genes (including DNA-PKcs , Lig4 and Xrcc4 ) were reduced in B cells of these mice [52] and this was accompanied by impaired class switch recombination [53], a process that depends on proper NHEJ.…”

Oropharyngeal squamous cell carcinoma in the veteran population: Association with traditional carcinogen exposure and poor clinical outcomes

“…Clinical outcomes for this group of patients have remained largely unchanged over the last 40 years, despite advances in treatment strategies . We have recently completed a detailed analysis of patients diagnosed with laryngeal SCC at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) . Our analysis demonstrated that veterans with laryngeal SCC are older and have a more extensive carcinogen exposure than is encountered in the general population .…”