DNA Replication, Cancer and Chemotherapy

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications, trials & patents

Abstract

GENES, in press Developmental Acquisition of p53 Functions Sushil K. Jaiswal, Sonam Raj and Melvin L. DePamphilis Remarkably, the p53 transcription factor, referred to as the guardian of the genome, is not essential for mammalian development. Moreover, efforts to identify p53 dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53 dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during early gastrulation, and that DNA damage induced apoptosis does not depend on p53. CANCER RESEARCH. 2021 Jun 1;81(11):2903-2917. Combined Inhibition of p38MAPK and PIKfyve Synergistically Disrupts Autophagy to Selectively Target Cancer Cells Constandina E O'Connell, Alex Vassilev (work done in M.L. DePamphilis lab) PMID: 33685990 This study demonstrates that PIKfyve and p38MAPK cooperate to regulate lysosome homeostasis and their combined inhibition synergistically blocks autophagy to reduce cancer cell viability in vitro and in vivo. STEM CELLS. 2020 Sep;38(9):1091-1106. Cell cycle arrest and apoptosis are not dependent on p53 prior to p53-dependent embryonic stem cell differentiation Sushil K Jaiswal, John J Oh, Melvin L DePamphilis PMID: 32478947 Previous efforts to determine whether or not the transcription factor and tumor suppressor protein p53 is required for DNA damage-induced apoptosis in pluripotent embryonic stem cells (ESCs) produced contradictory conclusions. The results presented here reveal that the multiple roles of p53 in cell cycle regulation and apoptosis are first acquired during pluripotent stem cell differentiation. PLOS ONE. 2020 Mar 31;15(3):e0230670. Efficacy of a small molecule inhibitor of the transcriptional cofactor PC4 in prevention and treatment of non-small cell lung cancer Yan Zhang, Andrei Pavlov, Sohail Malik, Hong Chen, Nancy Kim, Ziqing Li, Xiaohong Zhang, Melvin L DePamphilis, Robert G Roeder, Hui Ge PMID: 32231397 The human positive coactivator 4 (PC4) was originally identified as a multi-functional cofactor capable of mediating transcription activation by diverse gene- and tissue-specific activators. These results demonstrated that AG-1031 could be a potential therapy for PC4-positive NSCLC. US Patent Application Number 63/119,522 (November 30, 2020) Therapeutics Against Pathogenic Coronaviruses Melvin L. DePamphilis, Arup Chakraborty and Matthew Frieman PIKfyve specific inhibitors can prevent SARS-CoV-2 infection of human cells without toxicity to normal human cells. CANCER RESEARCH. 2019 Oct 1;79(19):4896-4910. The Cdk2-c-Myc-miR-571 Axis Regulates DNA Replication and Genomic Stability by Targeting Geminin Yi Zhang, Zhuqing Li, Qiang Hao, Wei Tan, Jing Sun, Jing Li, Chi-Wei Chen, Zongzhu Li, Yunxiao Meng, Yuan Zhou, Zhiyong Han, Huadong Pei, Melvin L DePamphilis, Wenge Zhu PMID: 31431461 DNA rereplication leads to genomic instability and has been implicated in the pathology of a variety of human cancers. Eukaryotic DNA replication is tightly controlled to ensure it occurs only once during each cell cycle. Geminin is a critical component of this control, it prevents DNA rereplication from occurring during S, G2, and early M phases by preventing MCM helicases from forming prereplication complexes. These findings identify a novel regulatory mechanism that is critical for maintaining genome integrity by regulating DNA replication and cell-cycle progression. AUTOPHAGY. 2019 Oct;15(10):1694-1718. A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis Gaurav Sharma, Carlos M Guardia, Ajit Roy, Alex Vassilev, Amra Saric, Lori N Griner, Juan Marugan, Marc Ferrer, Juan S Bonifacino, Melvin L DePamphilis PMID: 30806145 High-throughput screening identified 5 chemical analogs (termed the WX8-family) that disrupted 3 events in lysosome homeostasis: (1) lysosome fission via tubulation without preventing homotypic lysosome fusion; (2) trafficking of molecules into lysosomes without altering lysosomal acidity, and (3) heterotypic fusion between lysosomes and autophagosomes. Remarkably, these compounds did not prevent homotypic fusion between lysosomes, despite the fact that homotypic fusion required some of the same machinery essential for heterotypic fusion. The results presented here show that the WX8-family of PIKFYVE inhibitors provides a basis for developing drugs that could selectively kill autophagy-dependent cancer cells, as well as increasing the effectiveness of established anti-cancer therapies through combinatorial treatments. ONCOGENE. 2019 Mar;38(13):2364-2379. DHS (trans-4,4'-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2) Chi-Wei Chen, Yongming Li, Shuya Hu, Wei Zhou, Yunxiao Meng, Zongzhu Li, Yi Zhang, Jing Sun, Zhou Bo , Melvin L DePamphilis, Yun Yen, Zhiyong Han, Wenge Zhu PMID: 30518875 DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. The results presented here show that DHS (trans-4,4'-dihydroxystilbene) is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest c