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Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells - PubMed

️Mon Jan 01 2024

Review

Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells

Jian Xu et al. Cells. 2024.

Abstract

Self-renewal and differentiation are two characteristics of hematopoietic stem cells (HSCs). Under steady physiological conditions, most primitive HSCs remain quiescent in the bone marrow (BM). They respond to different stimuli to refresh the blood system. The transition from quiescence to activation is accompanied by major changes in metabolism, a fundamental cellular process in living organisms that produces or consumes energy. Cellular metabolism is now considered to be a key regulator of HSC maintenance. Interestingly, HSCs possess a distinct metabolic profile with a preference for glycolysis rather than oxidative phosphorylation (OXPHOS) for energy production. Byproducts from the cellular metabolism can also damage DNA. To counteract such insults, mammalian cells have evolved a complex and efficient DNA damage repair (DDR) system to eliminate various DNA lesions and guard genomic stability. Given the enormous regenerative potential coupled with the lifetime persistence of HSCs, tight control of HSC genome stability is essential. The intersection of DDR and the HSC metabolism has recently emerged as an area of intense research interest, unraveling the profound connections between genomic stability and cellular energetics. In this brief review, we delve into the interplay between DDR deficiency and the metabolic reprogramming of HSCs, shedding light on the dynamic relationship that governs the fate and functionality of these remarkable stem cells. Understanding the crosstalk between DDR and the cellular metabolism will open a new avenue of research designed to target these interacting pathways for improving HSC function and treating hematologic disorders.

Keywords: DNA damage repair (DDR); Fanconi anemia (FA) pathway; cellular metabolism; hematopoietic stem cells (HSCs).

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
Metabolism in HSCs. Quiescent HSCs preferably utilize glycolysis rather than OXPHOS for energy production. During HSC differentiation and maturation, a rapid switch from glycolysis to mitochondrial OXPHOS and ATP generation occurs. Other metabolism pathways, including fatty acid metabolism, purine and amino acid metabolism, and cholesterol metabolism also participate to fine-tune the stemness and cell fate commitments of HSCs.

**Figure 2**
The FA proteins function in DNA damage repair. Eight of the FA proteins (namely FANCA, B, C, E, F, G, L, and M) form the FA core complex to mono-ubiquitinate two downstream FA proteins, FANCD2 and FANCI, upon DNA damage. The two then form a dimer to recruit other downstream FA proteins, such as FANCD1, FANCJ, and FANCN, to the damaged DNA and influence the DNA replication, cell-cycle control, and DNA repair processes.

**Figure 3**
p53 participates in the FA HSC metabolism. p53 regulates energy metabolism at the glycolytic and OXPHOS steps via the transcriptional regulation of its downstream genes, such as the synthesis of cytochrome c oxidase (SCO2), and inhibits glycolysis by negatively regulating the TP53-induced glycolysis regulator (TIGAR). FA HSCs are more dependent on OXPHOS and undergo a glycolysis-to-OXPHOS switch mediated by SCO2 under oxidative stress (Route 1). p53-TIGAR metabolic axis-mediated glycolytic suppression plays a compensatory role in attenuating DNA damage and proliferative exhaustion in FA HSCs (Route 2).

**Figure 4**
FANCD2 and HES1 act in concert to suppress inflammation-induced PPARγ to prevent HSC exhaustion through restricting fatty acid oxidation (FAO). (A). Loss of *Hes1* deregulates genes in PPARγ signaling and FAO, thereby augment FAO in HSPCs. (B). A novel FANCD2/HES1/PPARγ axis constitutes a key component of immunemetabolic regulation, connection inflammation, cellular metabolism and HSC function.

**Figure 5**
The FA pathway and mitochondria. FANCD2 localizes in the mitochondrion and associates with the nucleoid complex components Atad3 and Tufm, linking the FA pathway and mitochondrial homeostasis.

Cited by

HES1 is required for mouse fetal hematopoiesis.
Zhu AZ, Ma Z, Wolff EV, Lin Z, Gao ZJ, Li X, Du W. Zhu AZ, et al. Stem Cell Res Ther. 2024 Jul 29;15(1):235. doi: 10.1186/s13287-024-03836-8. Stem Cell Res Ther. 2024. PMID: 39075526 Free PMC article.
Somatic gene mutations involved in DNA damage response/Fanconi anemia signaling are tissue- and cell-type specific in human solid tumors.
Rai SK, Du W, Zhang J, Yu H, Deng Y, Fei P. Rai SK, et al. Front Med (Lausanne). 2024 Oct 3;11:1462810. doi: 10.3389/fmed.2024.1462810. eCollection 2024. Front Med (Lausanne). 2024. PMID: 39421870 Free PMC article.

References

1. Eaves C.J. Hematopoietic stem cells: Concepts, definitions, and the new reality. Blood. 2015;125:2605–2613. doi: 10.1182/blood-2014-12-570200. - DOI - PMC - PubMed
1. Orkin S.H., Zon L.I. Hematopoiesis: An evolving paradigm for stem cell biology. Cell. 2008;132:631–644. doi: 10.1016/j.cell.2008.01.025. - DOI - PMC - PubMed
1. Li X., Sipple J., Pang Q., Du W. Salidroside stimulates DNA repair enzyme Parp-1 activity in mouse HSC maintenance. Blood. 2012;119:4162–4173. doi: 10.1182/blood-2011-10-387332. - DOI - PMC - PubMed
1. Morganti C., Cabezas-Wallscheid N., Ito K. Metabolic Regulation of Hematopoietic Stem Cells. HemaSphere. 2022;6:e740. doi: 10.1097/hs9.0000000000000740. - DOI - PMC - PubMed
1. Moretton A., Loizou J.I. Interplay between Cellular Metabolism and the DNA Damage Response in Cancer. Cancers. 2020;12:2051. doi: 10.3390/cancers12082051. - DOI - PMC - PubMed

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Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells - PubMed