bims-ershed 2022-05-22 papers

Cardiovasc Res. 2022 May 16. pii: cvac080. [Epub ahead of print]

Targeting DNA damage response in cardiovascular diseases: from pathophysiology to therapeutic implications.

Lin Wu, James R Sowers, Yingmei Zhang, Jun Ren.

Cardiovascular diseases (CVDs), arise from a complex interplay among genomic, proteomic, and metabolomic abnormalities. Emerging evidence has recently consolidated the presence of robust DNA damage in a variety of cardiovascular disorders. DNA damage triggers a series of cellular responses termed DNA damage response (DDR) including detection of DNA lesions, cell cycle arrest, DNA repair, cellular senescence and apoptosis, in all organ systems including hearts and vasculature. Although transient DDR in response to temporary DNA damage can be beneficial for cardiovascular function, persistent activation of DDR promotes the onset and development of CVDs. Moreover, therapeutic interventions that target DNA damage and DDR have the potential to attenuate cardiovascular dysfunction and improve disease outcome. In this review, we will discuss molecular mechanisms of DNA damage and repair in the onset and development of CVDs, and explore how DDR in specific cardiac cell types contributes to CVDs. Moreover, we will highlight the latest advances regarding the potential therapeutic strategies targeting DNA damage signaling in CVDs.

Keywords: Cardiovascular disease; DNA damage; DNA damage response; DNA repair; Therapeutics

DOI: https://doi.org/10.1093/cvr/cvac080

Nat Plants. 2022 May;8(5): 481-490

Transcriptional competition shapes proteotoxic ER stress resolution.

Dae Kwan Ko, Federica Brandizzi.

Through dynamic activities of conserved master transcription factors (mTFs), the unfolded protein response (UPR) relieves proteostasis imbalance of the endoplasmic reticulum (ER), a condition known as ER stress1,2. Because dysregulated UPR is lethal, the competence for fate changes of the UPR mTFs must be tightly controlled3,4. However, the molecular mechanisms underlying regulatory dynamics of mTFs remain largely elusive. Here, we identified the abscisic acid-related regulator G-class bZIP TF2 (GBF2) and the cis-regulatory element G-box as regulatory components of the plant UPR led by the mTFs, bZIP28 and bZIP60. We demonstrate that, by competing with the mTFs at G-box, GBF2 represses UPR gene expression. Conversely, a gbf2 null mutation enhances UPR gene expression and suppresses the lethality of a bzip28 bzip60 mutant in unresolved ER stress. By demonstrating that GBF2 functions as a transcriptional repressor of the UPR, we address the long-standing challenge of identifying shared signalling components for a better understanding of the dynamic nature and complexity of stress biology. Furthermore, our results identify a new layer of UPR gene regulation hinged upon an antagonistic mTFs-GFB2 competition for proteostasis and cell fate determination.

DOI: https://doi.org/10.1038/s41477-022-01150-w

J Exp Biol. 2022 May 16. pii: jeb.244145. [Epub ahead of print]

Activation of p53 in anoxic freshwater crayfish, Faxonius virilis.

Aakriti Gupta, Sarah A Breedon, Kenneth B Storey.

Tumor suppressing transcription factor p53 regulates multiple pathways including DNA repair, cell survival, apoptosis, and autophagy. The current work studies stress-induced activation of p53 in anoxic crayfish (Faxonius virilis). Relative levels of target proteins and mRNAs involved in the DNA damage response was measured in normoxic control and anoxic hepatopancreas and tail muscle. Phosphorylation levels of p53 was assessed using immunoblotting at sites known to be phosphorylated (Serine 15 and 37) in response to DNA damage or reduced oxygen signaling. The capacity for DNA binding by phospho-p53 was also measured, followed by transcript analysis of a potentially pro-apoptotic downstream target, the etoposide induced (ei24) gene. Following this, both inhibitor (MDM2) and activator (p19-ARF) protein levels in response to low oxygen stress were studied. The results showed an increase in p53 levels during anoxia in both hepatopancreases and tail muscle. Increased transcript levels of ei24, a downstream target of p53, support the activation of p53 under anoxic stress. Cytoplasmic accumulation of Ser-15 p-p53 was observed during anoxia when proteins from cytoplasmic and nuclear fractions were measured. Increased cytoplasmic concentration is known to initiate an apoptotic response, which can be assumed as a preparatory step to prevent autophagy. The results suggest that p53 might play a protective role in crayfish defense against low oxygen stress. Understanding how anoxia-tolerant organisms are able to protect against DNA damage could provide important clues towards survival under metabolic rate depression and preparation for recovery to minimize damage.

Keywords: Anoxia; Apoptosis; Crayfish; DNA damage; Metabolic rate depression; Stress tolerance

DOI: https://doi.org/10.1242/jeb.244145

Mol Oncol. 2022 May 18.

Targeting the DNA damage response and repair in cancer through nucleotide metabolism.

Thomas Helleday, Sean G Rudd.

Exploitation of the DNA damage response and DNA repair proficiency of cancer cells is an important anti-cancer strategy. The replication and repair of DNA is dependent upon the supply of deoxynucleoside triphosphate (dNTP) building blocks, which are produced and maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic DNA lesions in cancer cells. These same pathways also activate antimetabolites, an important group of chemotherapies that disrupt both nucleotide and DNA metabolism to induce DNA damage in cancer cells. Thus, dNTP metabolic enzymes can also be targeted to refine the use of these chemotherapeutics, many of which remain standard-of-care in common cancers. In this review article, we will discuss both these approaches exemplified by the enzymes MTH1, MTHFD2, and SAMHD1.

Keywords: Cancer; DNA damage response; MTH1; MTHFD2; SAMHD1; dNTP metabolism

DOI: https://doi.org/10.1002/1878-0261.13227

Front Aging Neurosci. 2022 ;14 786420

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis.

Anna Konopka, Julie D Atkin.

DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the "DNA damage response." Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.

Keywords: ALS; C9orf72; DNA damage; DNA repair; FUS; TDP-43; amyotrophic lateral sclerosis

DOI: https://doi.org/10.3389/fnagi.2022.786420