Why normal cells turn into cancer cells? One of the factors is deeply related to the failure of the cell differentiation mechanism called DNA methylation (*1) . The joint research groups of The Institute of Medical Science, the University of Tokyo, Yokohama City University, and Center for Integrated Protein Science Munich (CIPSM) have clarified new mechanism for controlling DNA methylation in cells.
Ubiquitination(*2) of a protein called PAF15(*3) is an important factor for the inheritance of DNA methylation, according to the new research. The group also successfully demonstrated a molecular mechanism by which PAF15 is ubiquitinated. In this way, the group revealed the mechanism underlying how cellular memory is inherited when cells proliferate.
The research was published in Nature communications (online version, March 6, 2020). The results are expected to greatly contribute to applications in this field, such as the development of new inhibitors of DNA methyltransferase that specifically target cancer cells.
The primary mechanism of this DNA methylation has not been fully elucidated
PAF15 is a factor guaranteeing the maintenance of DNA methylation
Further analysis revealed that PAF15 binds to chromosomes via PCNA(*7) during DNA replication, The research group also showed that two lysine residues of PAF15 undergo monoubiquitination by UHRF1(*8) to facilitate DNMT1 chromatin localization. These results indicate that PAF15 is an important regulator of DNMT1.
Potential to greatly contribute to the development of DNA methylase inhibitors
(*2) ubiquitination: the reaction that covalently conjugates a small polypeptide, ubiquitin, to a particular residue of a target protein. Ubiquitination affects protein stability, cellular localization, enzymatic activity, and protein-protein interactions.
(*3) PAF15: PCNA-associated factor 15 was identified as a proliferating nuclear antigen interacting protein.
(*4) epigenetic mutation: defined as aberrant DNA methylation and histone modifications.
(*5) histone modification: Covalent post-translational modification to histone proteins, which includes methylation, acetylation, and ubiquitination. These modifications cooperate with DNA methylation to impact gene expression and chromatin structure.
(*7) PCNA: Proliferating cell nuclear antigen (PCNA) is a critical regulator of DNA replication, which regulates DNA polymerase processivity.
(*8) UHRF1: Ubiquitin-like, PHD and RING finger containing 1 plays a critical role in the maintenance of DNA methylation. UHRF1 specifically binds to hemi-methylated DNA during S-phase and recruits DNMT1 to sites of DNA methylation.
About the research
PapersArticle URL: https://www.nature.com/articles/s41467-020-15006-4
Related LinksThe Institute of Medical Science, The University of Tokyo
Yokohama City University
Center for Integrated Protein Science Munich (CIPSM)