Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability

Abstract

BackgroundNEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage.ResultsWe show here that NEK1-deficient cells suffer major errors in mitotic chromosome segregation and cytokinesis, and become aneuploid. These NEK1-deficient cells transform, acquire the ability to grow in anchorage-independent conditions, and form tumors when injected into syngeneic mice. Genomic instability is also manifest in NEK1 +/- mice, which late in life develop lymphomas with a much higher incidence than wild type littermates.ConclusionNEK1 is required for the maintenance of genome stability by acting at multiple junctures, including control of chromosome stability.

Nek1 kinase associates with ATR–ATRIP and primes ATR for efficient DNA damage signaling

“…Nek1 −/− mutant mice displayed several phenotypes similar to those of the hypomorphic ATR-Seckel mutant mice, such as dwarfism, sterility, and anemia (37). Similar to some Seckel patients, Nek +/− mutant mice developed lymphoma (38,39). Interestingly, loss of Nek1 has been linked to defective ciliogenesis and progressive kidney failure in both mouse and human (40)(41)(42)(43).…”

Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

“…Its protein product is a dual serine-threonine and tyrosine kinase required for efficient DNA damage checkpoint activation and for maintaining chromosome stability. 42 Moreover, there is evidence to suggest that NEK1 functions as a tumor suppressor. 42 In the present study, 2 of 93 high-risk PC families were found to carry a novel NEK1 :p.Ala563Tyrfs*36 variant.…”

Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

“…47 The functional and pathological roles of these newly discovered genetic alterations in the context of cHL are yet to be determined; this is challenging because of the lack of cHL animal models or cell culture systems that include the tumor cell microenvironment. The role of B2M in cHL pathogenesis deserves particular mention.…”