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Age-related dysfunction of the DNA damage response in intestinal stem cells.

ABSTRACT: Background:Senescence increases the risks of inflammatory bowel diseases and colon cancer. Intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. However, the influence of aging on the functions of ISCs is largely unknown. The mutation rate is highest in the small and large intestines. Numerous types of naturally occurring DNA damage are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. This study investigated whether aging affects the DDR in mouse ISCs. Methods:Young (2-3-month-old) and old (>?19-month-old) Lgr5-EGFP-IRES-creERT2 mice were irradiated. The DDR in Lgr5-positive ISCs was compared between these mice by immunohistochemical analyses. Results:Induction of DDR marker proteins (phosphorylated ATR and 53BP1), inflammatory factors (phosphorylated NF-?B and interleukin-6), and a mitochondrial biogenesis-associated gene (peroxisome proliferator-activated receptor-? coactivator 1?) was lower in old ISCs than in young ISCs in vivo. Conclusion:The competence of the DDR in ISCs declines with age in vivo.

SUBMITTER: Watanabe K

PROVIDER: S-EPMC6485179 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Age-related dysfunction of the DNA damage response in intestinal stem cells.

Watanabe Koichiro K Ikuno Yasuaki Y Kakeya Yumi Y Ikeno Shinsuke S Taniura Hitomi H Kurono Masayoshi M Minemori Keito K Katsuyama Yu Y Naka-Kaneda Hayato H

Inflammation and regeneration 20190426

<h4>Background</h4>Senescence increases the risks of inflammatory bowel diseases and colon cancer. Intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. However, the influence of aging on the functions of ISCs is largely unknown. The mutation rate is highest in the small and large intestines. Numerous types of naturally occurring DNA damage are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosi ...[more]

PMID: 31057688

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Project description:Abstract: Protein homeostasis (proteostasis) is critical for cell function, and its decline is proposed as a hallmark of aging. Somatic stem cells (SCs) have a unique ability to maintain their proteostatic capacity, yet mechanisms to achieve this remain incompletely understood. Here, we describe and characterize a ‘proteostatic checkpoint’ in Drosophila intestinal SCs (ISCs). Following a breakdown of proteostasis, ISCs coordinate cell cycle arrest with protein aggregate clearance by Atg8-mediated activation of the Nrf2-like transcription factor cap-n-collar C (CncC), which induces the cell cycle inhibitor Dacapo and proteolytic genes. The capacity to engage this checkpoint is lost in ISCs from aging flies, and we show that it can be restored by treating flies with an Nrf2 activator, or by over-expression of CncC or Atg8a. This limits age-related intestinal barrier dysfunction and can result in lifespan extension. Our findings identify a new mechanism by which somatic SCs preserve proteostasis, and highlight potential intervention strategies to maintain regenerative homeostasis. Purpose of Study: To explore the transcriptional program downstream of CncC in Drosophila ISCs in more detail, we performed RNAseq analysis on FACS-purified wild-type or CncC-deficient escargot-positive cells (ISCs/EBs) in which the proteostatic checkpoint was engaged through the expression of HttQ138 or through the knockdown of rpn3. Results: While knockdown of rpn3 resulted in a more pronounced and broader transcriptional response than the expression of HttQ138, 93 of the 200 genes that were induced by HttQ138 expression (using a cut-off of 3-fold induction and a minimum expression of 10 FPKM) were also induced by knockdown of rpn3, illustrating a broad overlap of transcriptional changes elicited by the two conditions. Induction of 167 of those 200 genes was dependent on CncC. GO analysis of either the 93 genes induced in both stress conditions, or of the 167 CncC-dependent genes revealed a significant enrichment of genes encoding proteins involved in proteolysis and protein metabolism.

Dataset Information

Age-related dysfunction of the DNA damage response in intestinal stem cells.

Publications

Age-related dysfunction of the DNA damage response in intestinal stem cells.

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