Biology subjects

Marmolejo, C. O.

Publications and source records attributed to Marmolejo, C. O..

3 recordsLinked to original sources

bioRxiv2026

G2-to-G0 cell cycle exit underlies sensitivity to ATR inhibition via the p53-p21-RB1 axis

Ataxia-telangiectasia and Rad3-related (ATR) is an essential DNA damage response kinase that protects genome integrity by controlling cell cycle checkpoints, regulating origin firing, stabilizing replication forks, and signaling DNA repair. Due to hyper-proliferation, cancer cells depend on ATR for survival, implicating ATR inhibitors as promising therapeutics. However, variable tumor responses to ATR inhibitors highlights the need to uncover the determinants of cell fate. Here, we show breast cancer sensitivity to ATR inhibition correlates with the appearance of pan-nuclear DNA damage. The fate of these cells is driven by a p53-p21-RB1 axis that triggers a G2-to-G0-like cell cycle exit and is buffered by the p53 inhibitor MDM2. MDM2 inhibition lowers the DNA damage threshold for cell cycle exit and robustly targets ATR inhibitor-resistant cells. Our work reveals cell cycle plasticity as a mechanism determining cell fate during ATR inhibition and identifies MDM2 as a target for increasing ATR inhibitor efficacy.

molecular biology↗

bioRxiv2025

HMG box-containing protein 1 (HBP1) prevents pancreatic injury in experimental pancreatitis but accelerates pancreatic neoplasia progression

Background & AimsPancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG- box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. MethodsWe examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared to their littermate controls. Spatial transcriptomics and multiplexed protein assays, histological analysis, and immunostaining were utilized to characterize pathological changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. ResultsHBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. ConclusionsHBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.

cell biology↗

bioRxiv2024

A phosphorylation code coordinating transcription condensate dynamics with DNA replication

Chromatin is organized into compartments enriched with functionally-related proteins driving non-linear biochemical activities. Some compartments, e.g. transcription foci, behave as liquid condensates. While the principles governing the enrichment of proteins within condensates are being elucidated, mechanisms that coordinate condensate dynamics with other nuclear processes like DNA replication have not been identified. We show that at the G1/S cell cycle transition, large transcription condensates form at histone locus bodies (HLBs) in a cyclin-dependent kinase 1 and 2 (CDK1/2)-dependent manner. As cells progress through S phase, ataxia-telangiectasia and Rad3-related (ATR) accumulates within HLBs and dissolves the associated transcription condensates. Integration of CDK1/2 and ATR signaling creates a phosphorylation code within the intrinsically-disordered region of mediator subunit 1 (MED1) coordinating condensate dynamics with DNA replication. Disruption of this code results in imbalanced histone biosynthesis, and consequently, global DNA damage. We propose the spatiotemporal dynamics of transcription condensates are actively controlled via phosphorylation and essential for viability of proliferating cells.

molecular biology↗