Biology subjects

Aumer, T.

Publications and source records attributed to Aumer, T..

3 recordsLinked to original sources

bioRxiv2025

Increasing TET expression and 5-hydroxymethylcytosine formation by a carbocyclic 5-aza-2'-deoxy-cytidine antimetabolite

Ten-eleven translocation (TET) enzymes are critical epigenetic regulators, which oxidize the methylated cytosine nucleobase 5-methyl-dC (5mdC) in the genome to 5-hydroxymethyl-dC (5hmdC) in an -ketoglutarate-dependent manner. Because the presence of 5mdC in the promoter region of a given gene silences its expression, this oxidation goes in hand with the reactivation of such silenced genes. In different highly aggressive cancers such as acute myeloid leukemia (AML) and glioblastoma, loss of TET enzyme function and therefore reduced 5hmdC levels pave the way for tumor development. Impairment of TET activity can occur through metabolic inhibition, through loss-of-function mutations in TET genes themselves, and finally through suppression of TET-expression via epigenetic silencing. Reactivation of TET enzyme expression represents a major aim of epigenetic cancer therapy. Here we show that the carbocyclic antimetabolite 5-aza-2deoxycytidine (cAzadC), which is supposed to suppress the methylation of DNA during replication, leads to a substantial increase of TET2 expression and strongly increasing 5hmdC levels. We show that the treatment with cAzadC goes in hand with the broad reactivation of the cellular anti-tumor responses. With patient-derived xenograft AML-mouse models, we show that this translates into a strongly improved anti-cancer effect in vivo.

cancer biology↗

bioRxiv2023

The type of DNA damage response after Decitabine treatment depends on the level of DNMT activity

Decitabine and Azacytidine are considered as epigenetic drugs that induce DNA- methyltransferase (DNMT)-DNA crosslinks, resulting in DNA-hypomethylation and -damage. Although they are applied against myeloid cancers, important aspects of their mode of action remain unknown, which highly limits their clinical potential. Using a combinatorial approach, we reveal that the efficacy profile of both compounds primarily depends on the level of induced DNA-damage. Under low DNMT-activity, only Decitabine has a substantial impact. Conversely, when DNMT-activity is high, toxicity and cellular response to both compounds are dramatically increased, but do not primarily depend on DNA-hypomethylation or RNA-associated processes, contradicting an RNA-dependent effect of Azacytidine. By applying spatial proteomics, we show that Decitabine induces a strictly DNMT-dependent multifaceted DNA- damage response based on chromatin-recruitment of various repair-associated proteins. The choice of DNA-repair pathway herby depends on the severity of Decitabine-induced DNA- lesions. While mismatch (MMR) and base-excision DNA repair (BER) as well as RAD50- dependent DNA double-strand break repair are always activated in response to Decitabine, Fanconi anemia-dependent DNA-repair combined with homologous recombination is only activated when DNMT-activity is moderate. In contrast, high DNMT-activity and therefore immense replication stress, induce DNA repair by non-homologous and alternative end-joining.

biochemistry↗

bioRxiv2022

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2-deoxycytidine by methylating 2-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity towards AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response towards AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.

molecular biology↗