Biology subjects

Starrett, G.

Publications and source records attributed to Starrett, G..

3 recordsLinked to original sources

bioRxiv2026

Therapeutic-induced chromatin remodeling via AP-1/SWI-SNF enhances BK Polyomavirus replication in urothelial cells

Hemorrhagic cystitis (HC) caused by BK polyomavirus (BKPyV) reactivation is a serious complication in immunocompromised patients especially in hematopoietic stem cell transplant recipients, yet the effects of conditioning regimens on viral replication remain undefined. Current therapies for HC are largely supportive, and no specific antiviral drugs are approved for BKPyV reactivation, underscoring an urgent need for new interventions. Here, using a cellular model of HC, we provide the first mechanistic evidence that physiologic concentrations of genotoxic chemotherapy, immune-conditioning, and antiviral exposures commonly enhance BKPyV replication by reprogramming host chromatin remodeling machinery independently of immune suppression. Transcriptomic and epigenomic profiling of urothelial cells revealed that these treatments induce host and virus chromatin remodeling, specifically, the SWI/SNF ATP-dependent remodeling complex is activated and creates a regulatory landscape enriched for AP-1 transcription factor motifs, implicating the AP-1/SWI-SNF axis as a key regulator of viral replication. Functional inhibition of SWI/SNF with AU-15330 and FHD-286 consistently suppressed BKPyV replication across all tested therapeutic conditions. Patient urine samples and cellular experiments demonstrated these effects are independent of viral genomic changes. These findings suggest chromatin remodeling as the mechanistic driver of therapy-associated BKPyV reactivation and propose SWI/SNF inhibition as a translational therapeutic strategy to mitigate hemorrhagic cystitis.

microbiology↗

bioRxiv2019

APOBEC3A Catalyzes Mutation and Drives Carcinogenesis In Vivo

The APOBEC3 family of antiviral DNA cytosine deaminases is implicated as the second largest source of mutation in cancer. This mutational process may be a causal driver or inconsequential passenger to the overall tumor phenotype. We show that human APOBEC3A expression in murine colon and liver tissues increases tumorigenesis. All other APOBEC3 family members including APOBEC3B did not as strongly promote liver tumor formation. DNA sequences from APOBEC3A-expressing animals display hallmark APOBEC signature mutations in TCA/T motifs. Bioinformatic comparisons of the observed APOBEC3A mutation signature in murine tumors, previously reported APOBEC3A and APOBEC3B mutation signatures in yeast, and reanalyzed APOBEC mutation signatures in human tumor data sets support cause-and-effect relationships for APOBEC3A-catalyzed deamination and mutagenesis in driving multiple human cancers.

cancer biology↗

bioRxiv2018

Polyomavirus T-Antigen Induces APOBEC3B Expression using a LXCXE-Dependent and TP53-Independent Mechanism

APOBEC3B is a single-stranded DNA cytosine deaminase with beneficial innate antiviral functions. However, misregulated APOBEC3B can also be detrimental by inflicting APOBEC signature C-to-T and C-to-G mutations in genomic DNA of multiple cancer types. Polyomaviruses and papillomaviruses use dominant oncoproteins to induce APOBEC3B overexpression, perhaps to their own benefit, but little is known about the cellular mechanisms hijacked by these viruses to do so. Here we investigate the molecular mechanism of APOBEC3B upregulation by the polyomavirus large T-antigen. First, truncated T-antigen (truncT) is sufficient for APOBEC3B upregulation and the RB interacting motif (LXCXE), but not the TP53 inhibition domain, is required. Second, upregulated APOBEC3B is strongly nuclear and partially localized to virus replication centers. Third, genetic knockdown of RB1 alone or in combination with RBL1 and/or RBL2 is insufficient to suppress truncT-mediated induction of APOBEC3B. Fourth, CDK4/6 inhibition by palbociclib is also insufficient to suppress truncT-mediated induction of APOBEC3B. Fifth, global gene expression analyses in a wide range of human cancers show significant associations between expression of APOBEC3B and other genes known to be regulated by the RB/E2F axis. These experiments combine to implicate the RB/E2F axis in promoting APOBEC3B transcription, yet they also suggest that the polyomavirus RB binding motif has in addition to RB inactivation at least one additional function for triggering APOBEC3B upregulation in virus-infected cells.\n\nIMPORTANCEThe APOBEC3B DNA cytosine deaminase is overexpresssed in many different cancers and correlated with elevated frequencies of C-to-T and C-to-G mutations in 5-TC motifs, oncogene activation, acquired drug resistance, and poor clinical outcomes. The mechanisms responsible for APOBEC3B overexpression are not fully understood. Here, we show that the polyomavirus truncated T-antigen (truncT) triggers APOBEC3B overexpression through its RB-interacting motif, LXCXE, which in turn likely enables one or more E2F family transcription factors to promote APOBEC3B expression. This work strengthens the mechanistic linkage between active cell cycling, APOBEC3B overexpression, and cancer mutagenesis. Although this mechanism damages cellular genomes, viruses may leverage it to promote evolution, immune escape, and pathogenesis. The cellular portion of the mechanism may also be relevant to non-viral cancers, where genetic mechanisms often activate the RB/E2F axis and APOBEC3B mutagenesis contributes to tumor evolution.

microbiology↗