Biology subjects

Madakashira, B. P.

Publications and source records attributed to Madakashira, B. P..

3 recordsLinked to original sources

bioRxiv2025

UHRF1 Overexpression Generates Distinct Senescent States with Different Tp53 Dependencies

SummarySenescence is a pleiotropic phenotype that alternatively suppresses or promotes cancer. The tumor suppressive roles are linked to clearance of damaged cells by the immune system, while cells with tumor promoting functions resist apoptosis, evade immune clearance and either persist and support the tumor microenvironment, or escape and proliferate. What generates these diverse populations is unclear. We investigated this in preneoplastic zebrafish livers where the epigenetic regulator, UHRF1, is overexpressed in hepatocytes. Double strand breaks, DNA methylation repatterning, retrotransposon expression, cell cycle withdrawal and activation of Atm and Tp53 dependent senescence were early responses to UHRF1 overexpression. This evolved to generate diverse populations of senescent cells, some which expressed immune and senescence signatures plus anti-apoptotic markers, and others co-expressed proliferative genes. The fate of these populations was dictated by UHRF1 levels and Tp53, as Tp53 loss enabled proliferation of cells with reduced UHRF1 expression but not in cells expressing high UHRF1. The senolytic Navitoclax targeted only a subset of senescent cells. Thus, the diversity of senescent cells driven by epigenetic changes can generate divergent outcomes. Short summaryUHRF1 overexpression in zebrafish hepatocytes induces DNA damage leading to Atm-tp53-dependent senescence with UHRF1 levels dictating whether hepatocytes remain senescent, escape, or undergo senolytic elimination.

cancer biology↗

bioRxiv2024

Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity

Tumor heterogeneity is the substrate for tumor evolution and the linchpin of treatment resistance. Cancer cell heterogeneity is largely attributed to distinct genetic changes within each cell population. However, the widespread epigenome repatterning that characterizes most cancers is also highly heterogenous within tumors and could generate cells with diverse identities and malignant features. We show that high levels of the epigenetic regulator and oncogene, UHRF1, in zebrafish hepatocytes rapidly induced methylome disordering, loss of heterochromatin, and DNA damage, resulting in cell cycle arrest, senescence, and acquisition of stemness. Reducing UHRF1 expression transitions these cells from senescent to proliferation-competent. The expansion of these damaged cells results in hepatocellular carcinomas (HCC) that have immature cancer cells intermingled with fibroblasts, immune and senescent cells expressing high UHRF1 levels, which serve as reservoirs for new cancer cells. This defines a distinct and heterogenous HCC subtype resulting from epigenetic changes, stemness and senescence escape.

cancer biology↗

bioRxiv2023

Cdk4/6 is activated by DNA hypomethylation to cause DNA rereplication and organ outgrowth defects

Coordinating epigenomic inheritance and cell cycle progression is essential for organogenesis. UHRF1 connects these functions by facilitating maintenance of DNA methylation and cell cycle progression. Here, we provide evidence resolving the paradoxical phenotype of uhrf1 mutant zebrafish embryos that have both activation of pro-proliferative E2F target genes and increased number of hepatocytes in S-phase, but the liver fails to grow. We find that Atr inhibition reduces DNA replication and increases liver size in uhrf1 mutants, suggesting that uhrf1 mutant hepatocytes have replication stress leading to Atr-mediated cell cycle inhibition and dormant origin firing. We uncover persistent Cdk4/6 activation as the mechanism driving uhrf1 mutant hepatocytes into S-phase, activating Atr and restricting hepatic outgrowth. Palbociclib treatment of uhrf1 mutant embryos prevented aberrant S-phase entry, and the DNA damage response. Palbociclib rescued most cellular and developmental phenotypes in uhrf1 mutants, except DNA hypomethylation, transposon activation and the interferon response. Pro-proliferative genes were also activated in a Cdk4/6 dependent fashion in the liver of dnmt1 mutants, suggesting DNA hypomethylation as a mechanism of Cdk4/6 activation. Thus, the developmental defects caused by DNA hypomethylation are attributed to persistent Cdk4/6 activation leading to DNA replication stress, dormant origin firing and cell cycle inhibition, preventing hepatic outgrowth.

developmental biology↗