Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila

Abstract

Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells’ environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11, Rad50, Nbs1, ATM, ATR, Chk1, and Chk2, which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly’s survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue-resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging.

Nutrient-Driven O-GlcNAcylation Controls DNA Damage Repair Signaling and Stem/Progenitor Cell Homeostasis

“…Interestingly, unlike the OGA knockdown, EC-specific OGT knockdown induced apoptosis (as indicated by caspase 3 cleavage; Figure S4D) and caused ISC hyperproliferation (as indicated by Delta staining; Figure S4I) and DNA damage accumulation (Figures S4E-S4H). Similarly, EC-specific DDR knockdown induced apoptosis in these cells, indicating that DDR is required for EC cell survival (Park et al, 2018). This apoptosis caused ISC hyperproliferation and accumulation of DNA damage.…”

Anti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells

“…It is well known that ECs surround ISCs [2,3] and they are a major source of niche signal on ISC self-renewal [60]. ECs are constantly exposed to external stresses, such as injury, infection, or damaged conditions, resulting in ECs death, which is a major cause of accelerated ISC proliferation [25,31,61,62]. A previous study reported that age-related loss of heterochromatin stability in differentiated ECs is associated with an increase of age-related phenotypes of ISC (hyperproliferation and DNA damage accumulation) through apoptotic death, as a niche aging [49].…”

“…ISC proliferation is activated by the intrinsic and extrinsic oxidative stresses that are caused by aging, infection, and high metabolic rate [6][7][8][25][26][27]. In aged and oxidative stressed guts, there is hyperproliferation, DNA damage accumulation, and increased centrosome amplification, which are hallmarks of cancer [7,8,[28][29][30][31]. Numerous studies have reported the intrinsic and extrinsic pathways that are associated with age-related changes in ISCs [4,7,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46].…”

Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells

“…However, the extent to which the genome integrity of adult stem cells isolated from older patients influences the efficacy and safety outcomes of autologous stem cell therapy remains unclear. Accumulating evidence indicates that aged stem cells exhibit genomic instability (Burkhalter, Rudolph, & Sperka, 2015), possibly due to a reduced capacity for repairing DNA damage induced by either endogenous or exogenous stimuli (Park, Jeon, Pyo, Kim, & Yoo, 2018;Rossi et al, 2007). However, most of this research has been conducted using DNA repair deficient mouse models or clinical samples donated by human progeria patients (Zhang et al, 2011).…”