Biology subjects

Larner, J. M.

Publications and source records attributed to Larner, J. M..

3 recordsLinked to original sources

bioRxiv2026

An auto-generated ADP-ribosyl-cysteine degron drives DTX2-dependent turnover of PARP7

The mono-ADP-ribosyltransferase PARP7 exerts negative feedback on androgen receptor (AR) signaling by generating an ADP-ribosyl-cysteine degron on AR that marks it for degradation. Here we show that the protein half-life of PARP7 is set by cysteine auto-ADP-ribosylation, providing a mechanism for temporal control of its feedback on AR-dependent transcription in prostate cancer cells. ADP-ribosyl-cysteine in the PARP7 catalytic domain constitutes a degron read by the E3 ligase DTX2, driving PARP7 polyubiquitination and proteasomal degradation. Thus, the same E3 is used to degrade both PARP7 and its substrate AR. Using label-free mass spectrometry, we identify the AP-1 factor c-JUN as a PARP7 substrate and show that ADP-ribosylated c-JUN accumulates upon DTX2 depletion. ADP-ribosyl degron formation is dependent on NAD+ availability since depleting NAD+ pharmacologically or under hypoxia prevents degron formation and stabilizes PARP7 in a catalytically constrained state that compromises its feedback activity. Correlations between PARP7 expression and hypoxia signatures in prostate tumors, together with sensitivity to the PARP7-selective inhibitor RBN-2397 across cancer lines, nominate hypoxic, NAD+ depleted contexts as heightened vulnerability to PARP7-targeting agents. Marking transcription factors for degradation by covalent ADP-ribosylation is emerging as a distinct mode of transcriptional control.

biochemistry↗

bioRxiv2022

Replicative Instability Drives Cancer Progression

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress have been shown to exhibit genomic instability and poor survival rates across tumor types. Here we utilize-omics data from two independent consortia to identify the genetic underpinnings of replication stress, therapy resistance, and primary carcinoma to brain metastasis in BRCA wildtype tumors. In doing so, we have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by genomic evolution secondary to replicative challenge. Our data supports a model whereby defective single-strand break repair, translesion synthesis, and non-homologous end joining effectors drive RIN. Collectively, we find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Statement of SignificanceDefining the genetic basis of genomic instability with wildtype BRCA repair effectors is a significant unmet need in cancer research. Here we identify and characterize a pan-cancer cohort of tumors driven by replicative instability (RIN). We find that RIN drives therapy resistance and distant metastases across multiple tumor types.

cancer biology↗

bioRxiv2020

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

Ionizing radiation-induced DSBs are repaired primarily by the Non-Homologous End Joining (NHEJ) pathway, but the details of how this is regulated in different chromatin contexts are far from understood. We have discovered a novel response to DSBs that promotes NHEJ selectively in euchromatin, based on a novel interaction between the EMT-inducing transcriptional repressor ZEB1, and the well-studied NHEJ-promoting DNA repair factor 53BP1. Using a number of approaches, we have discovered that the ZEB1-53BP1 association is amplified following exposure of cells to IR and that they co-localize at IR-induced foci (IRIF). Depletion of ZEB1 enhances radio-sensitivity and increases IR-induced chromosomal aberrations in an ATM-independent manner. The very rapid recruitment-within 2 seconds-of ZEB1 to euchromatic DSBs is like-wise ATM-independent, but DNA-PK-dependent and is required for subsequent recruitment of 53BP1. ZEB1 promotes NHEJ and inhibits HR through its homeodomain by inducing 53BP1-permissive, pro-NHEJ/anti-HR chromatin modifications. Lastly, depletion of ZEB1 increases hyper-resection at DSBs and inhibits physiological DSB repair. These results support the argument that ZEB1 plays an essential role in DSB repair in euchromatin by establishing a 53BP1-permissive/pro-NHEJ chromatin environment.

cancer biology↗