NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length

Abstract

Deficiency of NEIL3, a DNA repair enzyme, has significant impact on mouse physiology, including vascular biology and gut health, processes related to aging. Leukocyte telomere length (LTL) is suggested as a marker of biological aging, and shortened LTL is associated with increased risk of cardiovascular disease. NEIL3 has been shown to repair DNA damage in telomere regions in vitro . Herein, we explored the role of NEIL3 in telomere maintenance in vivo by studying bone marrow cells from atherosclerosis-prone NEIL3-deficient mice. We found shortened telomeres and decreased activity of the telomerase enzyme in bone marrow cells derived from Apoe −/− Neil3 −/− as compared to Apoe −/− mice. Furthermore, Apoe −/− Neil3 −/− mice had decreased leukocyte levels as compared to Apoe −/− mice, both in bone marrow and in peripheral blood. Finally, RNA sequencing of bone marrow cells from Apoe −/− Neil3 −/− and Apoe −/− mice revealed different expression levels of genes involved in cell cycle regulation, cellular senescence and telomere protection. This study points to NEIL3 as a telomere-protecting protein in murine bone marrow in vivo .

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

“…Similarly, c -MYC promotes hTERT deregulation, resulting in the reduction of telomere length, telomerase activity and cell proliferation [ 82 ]. Additionally, TERT can act as a transcription co-factor that regulates expression of several genes [ 77 ], which are summarized in Supplementary Table S1 [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 ,…”

Biological Functions of the DNA Glycosylase NEIL3 and Its Role in Disease Progression Including Cancer

“…Unlike other DNA glycosylases, NEIL3 has its structural properties and excels in the repair of bases, including favoring base damage at ssDNA, G-quadruplex, ICLs, replication forks and telomere sites, thus promoting cell cycle progression and cell proliferation. A series of studies have confirmed that Neil3 -/- would probably lead to decreased bone marrow hematopoietic capacity, autoimmune defects, cardiovascular disease (atherosclerosis, myocardial infarction, myocardial rupture) and neurological disorders [ 50 , 96 , 98 , 99 , 102 , 107 ]. On the other hand, unlike NEIL1/2, overexpression of NEIL3, in turn, significantly increased the frequency of mutations in somatic cells; public database analysis also showed that NEIL3 was significantly overexpressed in a variety of cancer tissues or cancer cells, suggesting that NEIL3 may be a carcinogenic gene.…”

“…Later, researchers also demonstrated that NEIL3 initiated the BER pathway by recruiting APE1 and POLB to telomeric DNA damage sites primarily during mitosis, which in turn repaired telomere damage [ 49 ]. In vivo experiments revealed that Apoe -/- Neil3 -/- mice had shortened telomeres and reduced telomerase activity in bone marrow cells compared to Apoe -/- mice, as shown by reduced bone marrow production and lower leukocyte levels in peripheral blood [ 50 ]. This study suggests that NEIL3 has a role in protecting the length of telomeres in bone marrow cells in vivo, but the authors did not delve into the specific mechanisms.…”

Erdr1 orchestrates macrophage polarization and determines cell fate via dynamic interplay with YAP1 and Mid1

“…Firstly, Erdr1 and Mid1 are closely linked in gene mapping, as they are neighbor genes located in the PAR region of the sex chromosomes X and Y in mice (32)(33)(34). Secondly, Mid1 is functionally linked to Erdr1 (19,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52) YAP1 (19,53,54), and YAP1 downstream genes such as CTGF (55), Cry61 (35,40,44,55),36,55), as shown by previous microarray data and experiments. Thirdly, Erdr1 and Mid1 are known to play a shared role in regulating YAP1 signature gene expression (36,55,56).…”