Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development

Abstract

N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1−/− mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1−/− mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1−/− mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa, an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.

Opposing regulation of METTL11A by its family members METTL11B and METTL13

“…CRISPR-Cas9 mediated METTL11A knockout in C2C12 myoblasts prevents their differentiation into myofibers and instead promotes osteoblastic phenotypes (8). Knockout of Mettl11A in mice results in premature ageing phenotypes, including depletion of the neural stem cell pools, neurodegeneration, and cognitive impairments (9). Despite identifying these important biological roles of METTL11A, we still do not have a thorough understanding of its upstream regulation.…”

Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner

“…Knockdown of NTMT1 caused mitotic defects in HeLa cells, decreased the colony formation of HCT116 colorectal cancer cells, and downregulated transcription factor ELK3 to repress migration of cervical cancer cells. ,,, Moreover, multiple studies have implied the regulatory roles of NTMT1 in maintaining stem cells. Specifically, NTMT1 knockout mice exhibit neuro­degeneration through dysregulation of RB protein and neural stem cells proliferation . Thus, cell-potent inhibitors would serve as valuable tools to probe the functions of NTMT1.…”

“…Specifically, NTMT1 knockout mice exhibit neurodegeneration through dysregulation of RB protein and neural stem cells proliferation. 14 Thus, cell-potent inhibitors would serve as valuable tools to probe the functions of NTMT1.…”

Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1

“…Besides, the α-N-terminal methylation of DDB2 facilitates its nuclear localization to cyclobutane pyrimidine dimer (CPD) foci [4]. In addition, NTMT1 has been implicated in regulating mitosis, DNA damage repair, stem cell maintenance, and cervical cancer cell proliferation and migration [1,[11][12][13]. Thus, cell-potent inhibitors would serve as valuable tools to study the functions and roles of NTMT1/2.…”

“…Molecules 2022, 27, x FOR PEER REVIEW 2 of 10 [1,[11][12][13]. Thus, cell-potent inhibitors would serve as valuable tools to study the functions and roles of NTMT1/2.…”