Biology subjects

Mertz, T. M.

Publications and source records attributed to Mertz, T. M..

3 recordsLinked to original sources

bioRxiv2026

Squamous-state excursions activate APOBEC3A in cancer

The cytidine deaminase APOBEC3A is a major endogenous mutagen in human cancer, yet is rarely captured in bulk tumor RNA or protein profiles despite the prominent mutational scars it leaves in cancer genomes. The origin of these episodic mutational bursts has remained unclear, with prevailing models emphasizing sustained inflammatory signaling. Here, we show that APOBEC3A is induced in a rare subpopulation of cancer cells engaging a transient squamous differentiation program, linking APOBEC3A mutagenesis to lineage-state plasticity rather than persistent inflammatory signaling. Across breast and lung cancer cell lines and patient tumors, keratinocyte differentiation markers, including the stress keratins KRT6A and KRT16, are the strongest correlates of endogenous APOBEC3A expression. These days-long squamous-state excursions explain how APOBEC3A can leave durable mutational scars while remaining largely invisible to bulk tumor RNA and protein profiling. APOBEC3A catalytic activity reinforces selected components of this program through uracil excision and JNK-AP-1 signaling. The squamous differentiation transcription factor ZNF750 promotes APOBEC3A induction during squamous-state engagement in breast and lung cancer models. In established human squamous tumors, however, ZNF750 loss-of-function is associated with elevated APOBEC3A expression and APOBEC mutagenesis, revealing lineage-context-dependent regulation. These findings identify a transient differentiation state as a mutagenic intermediate, coupling cell-state plasticity to cancer genome evolution.

cancer biology↗

bioRxiv2026

APOBEC3A is the predominant global editor of cytosines in human mRNAs and in single-strand RNA viruses

APOBEC cytidine deaminases can convert cytosines to uracils in DNA as well as in RNA. The knowledge of DNA deamination motifs preferred by individual APOBECs revealed APOBEC3A as a major source of hypermutation in cancer. However, the extent and relative contribution of specific APOBECs into RNA editing remains unclear as their preferred RNA-editing motifs have not been defined. Here, using a parallel DNA and RNA sequencing strategy, coupled with motif-centered statistical analyses, we sought to identify mRNA edits and diagnostic editing motifs in yeast and human cells overexpressing individual APOBEC enzymes. This approach revealed a prevailing global enrichment for the uCg trinucleotide motif with even greater preference to the motifs cytosines located in 3 base of a loop within a hairpin-loop secondary structure when APOBEC3A, but not any other tested APOBEC, was overexpressed. Further analysis revealed the APOBEC3A-like diagnostic motif enrichment in editing calls from human cancers and blood cells. The APOBEC3A-like editing motif also prevailed in the RNA genomes of SARS-CoV-2 pandemic isolates, as well as in infectious persistent rubella viruses, and in polioviruses emerging from live-attenuated vaccine strains. Together, our results indicate that APOBEC3A is the predominant global APOBEC RNA editor with a potential to impact cell physiology and viral evolution.

genetics↗

bioRxiv2023

Genetic modifiers of APOBEC-induced mutagenesis

The cytidine deaminases APOBEC3A and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we utilized a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. Also, we determined whether each deletion was epistatic with UNG1 loss, which indicated whether the encoded factors participate in the error-free bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single stranded DNA (ssDNA). Additionally, we determined that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, which results in extremely high A3B-induced mutagenesis, (2) defective CTF18-RFC complex function, which results in high levels of A3B induced mutations specifically on the leading strand template that synergistically increase with loss of UNG1, and (3) defective HR-mediated bypass of APOBEC-induced lesions, which were epistatic with Ung1 loss and result from increased Rev1-mediated C-to-G substitutions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancer tumors display 3- to 4-fold more APOBEC-induced mutations. Mirroring our results in yeast, for BRCA1/2 deficient tumors Rev1-mediated C-to-G substitutions are solely responsible for increased APOBEC-signature mutations and these mutations occur on the lagging strand during DNA replication. Together these results identify important factors that influence the dynamics of DNA replication and likely the abundance of APOBEC-induced mutation during tumor progression as well as a novel mechanistic role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.

genomics↗