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

Tom Rune Karlsen; Maria B Olsen; Xiang Y Kong; Kuan Yang; Ana Quiles-Jiménez; Penelope Kroustallaki; Sverre Holm; Glenn Terje Lines; Pål Aukrust; Tonje Skarpengland; Magnar Bjørås; Tuva B Dahl; Hilde Nilsen; Ida Gregersen; Bente Halvorsen

doi:10.1016/j.bbrep.2022.101211

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

Biochem Biophys Rep. 2022 Jan 18:29:101211. doi: 10.1016/j.bbrep.2022.101211. eCollection 2022 Mar.

Authors

Tom Rune Karlsen^{1

2}, Maria B Olsen^{1

2}, Xiang Y Kong¹, Kuan Yang^{1

2}, Ana Quiles-Jiménez¹, Penelope Kroustallaki³, Sverre Holm¹, Glenn Terje Lines⁴, Pål Aukrust^{1

2

5}, Tonje Skarpengland^{1

5}, Magnar Bjørås^{6

7}, Tuva B Dahl^{1

8}, Hilde Nilsen³, Ida Gregersen¹, Bente Halvorsen^{1

2}

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
⁴ Simula Research Laboratory, Oslo, Norway.
⁵ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ Department of Microbiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁸ Department of Research and Development, Division of Emergencies and Critical Care, Oslo University Hospital HF, Rikshospitalet, Norway.

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.

Keywords: Hematopoiesis; NEIL3; Senescence; Telomeres.