Studies have proposed that oxi-mC bases are not only intermediates in the DNA demethylation process but may also serve as independent functional marks in the genome. 5hmC (the most abundant oxi-mC) is observed at sites of DNA damage and enriched at gene bodies as well as at enhancers where it correlates with gene expression and chromatin accessibility.
Our recent studies characterized the role of HMCES (5hmC binding protein in ES cell specific), which was originally identified bind oxi-mC marks, and revealed novel functions of HMCES in DNA double strand break (DNA DSB) repair by the Alternative end-joining (Alt-EJ) pathway (Molecular Cell, 2020). We collaborated with Drs. L. Aravind (NIH) and Cheryl Arrowsmith (University of Toronto) to study the structure-function relationship and identified single strand DNA binding activity of HMCES to be important for DNA repair by Alt-EJ pathway. Our findings highlighted further versatility in this ancient protein, and characterized HMCES as an important regulator in the Alt-EJ pathway, which is commonly implicated in generation of chromosomal translocations. We are now investigating the role of HMCES in regulation of B cell immune responses and pathogenesis of B cell malignancies.
