Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes


Autoři: Huanzhou Xu aff001;  Ramon D. Perez aff002;  Tiffany R. Frey aff001;  Eric M. Burton aff001;  Sudha Mannemuddhu aff003;  John D. Haley aff004;  Michael T. McIntosh aff005;  Sumita Bhaduri-McIntosh aff006
Působiště autorů: Division of Infectious Disease, Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America aff001;  Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New Yordk, Unites States of America aff002;  Division of Nephrology, Dept. of Pediatrics, University of Florida, Gainesville, Florida, United States of America aff003;  Department of Pathology and Stony Brook Proteomics Center, Stony Brook University, Stony Brook, New York, United States of America aff004;  Child Health Research Institute, Department of Pediatrics and of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America aff005;  Division of Infectious Disease, Departments of Pediatrics and of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America aff006
Vyšlo v časopise: Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes. PLoS Pathog 15(12): e1008228. doi:10.1371/journal.ppat.1008228
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008228

Souhrn

Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV’s ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers.

Klíčová slova:

B cells – Cell cycle and cell division – DNA repair – DNA replication – Epstein-Barr virus – Flow cytometry – Synthesis phase – Viral replication


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Hygiena a epidemiologie Infekční lékařství Laboratoř

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