Biology subjects

Krenz, B.

Publications and source records attributed to Krenz, B..

4 recordsLinked to original sources

bioRxiv2026

Selective repurposing of the eukaryotic DNA replication machinery by a plant virus

Eukaryotic DNA viruses that replicate in the nucleus often exploit components of the host DNA replication machinery for genome replication. Geminiviruses, causal agents of devastating crop diseases worldwide, strictly depend on host factors to replicate their circular single-stranded (ss) DNA genomes, with only a single virus-encoded protein, Rep, required for this process. Rep recruits host replication proteins to the viral genome and catalyzes nicking and ligation at the initiation and termination sites of rolling-circle replication. Despite the reliance of geminiviral replication on plant proteins, the composition of the viral replisome remains largely unknown. Here, we use TurboID-based proximity labeling to identify plant proteins in the vicinity of the Rep proteins from the geminiviruses tomato yellow leaf curl virus (TYLCV) and abutilon mosaic virus (AbMV) during infection. Combining virus-induced gene silencing, infection assays, and chromatin immunoprecipitation, we identify host DNA replication-related factors required for viral genome replication and likely components of the viral replisome. Our results indicate that geminiviruses and related eukaryotic ssDNA viruses selectively repurpose components of the eukaryotic replication fork to support rolling-circle replication, and suggest that they follow a leading-strand replication mode while utilizing the lagging-strand DNA polymerase {delta}. These findings shed light on the molecular mechanism of geminiviral DNA replication and identify potential targets for engineering antiviral resistance in crops.

plant biology↗

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Alternative splicing expands the functional portfolio of a plant virus to control the viral cycle

Viruses frequently have limited coding space, yet efficiently manipulate complex hosts by deploying intricate, often poorly understood strategies. Geminiviruses, devastating plant pathogens with small single-stranded (ss) DNA genomes, replicate in the nucleus aided by the viral replication-associated protein (Rep), the most conserved protein within this family and related ssDNA viruses. Rep initiates viral DNA replication and represses its own promoter to regulate the infection cycle. The molecular mechanisms enabling this dual functionality are so far unknown. Here, we show that the geminivirus tomato yellow leaf curl virus (TYLCV) exploits the host spliceosome to produce novel Rep splice variants. Splicing generates Rep isoforms lacking the central oligomerization domain that cannot initiate replication but strongly repress the Rep promoter. Conversely, Rep mutants deficient in splicing promote replication but fail to repress transcription. Reduced Rep splicing interferes with the viral gene expression hierarchy and decreases infectivity. Our findings therefore reveal a previously unrecognized viral strategy in which alternative splicing produces functionally specialized viral protein isoforms, providing a mechanistic explanation for the dual role of Rep in viral replication and gene regulation. Splicing events with potentially similar functional consequences in related viruses suggest that this strategy may have convergently evolved across diverse viral lineages infecting different domains of life.

plant biology↗

bioRxiv2024

RNA-mediated MYC multimerization suppresses innate immune signaling

In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition; the underlying mechanisms and their function are unknown. Here, we show that MYC re-localizes from its canonical location on DNA to RNA in response to the accumulation of intronic RNA. MYC binds RNA directly, which enhances its multimerization. MYC multimers concentrate the nuclear exosome, a 3-5 RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops, and promote exosome recruitment to R-loops. RNA binding of MYC suppresses activation of the innate immune kinase TBK1. Upon MYC depletion, intron-derived dsRNAs, including RNA derived from repetitive elements and small nucleolar RNAs, accumulate on TLR3, a pattern recognition receptor that activates TBK1. In MYC-depleted cells, TLR3-bound snoRNAs carry aberrant 3-ends, indicating defective exosomal processing. Our data show that the phase transition of MYC is a RNA-driven stress response that suppresses the accumulation of immunogenic RNAs.

molecular biology↗