CLARIFYING THE RELATIONSHIP BETWEEN PERICENTROMERIC HYPOMETHYLATION, DNA DAMAGE, AND MALIGNANCY: INSIGHTS FROM ZEBRAFISH MODELS OF IMMUNODEFICIENCY, CENTROMERE INSTABILITY, AND FACIAL ANOMALIES (ICF) SYNDROME

Hypomethylation of pericentromeric sequences is commonly observed in cancer, and it has been speculated that this hypomethylation may contribute to genome instability and aneuploidy. At present, the relationship between pericentromeric methylation and cancer is only correlative, and a causative role is yet to be established. Zebrafish models of ICF syndrome present an opportunity to dissect the relationship between pericentromeric hypomethylation, genome instability, and cancer. I aimed to test whether transcriptional signatures associated with DNA damage are associated with pericentromeric methylation loss and if ICF-like mutations lead to increased DNA damage susceptibility. Further, I examine if a pericentromeric hypomethylation is associated with decreased viability in a sensitized genetic background. We suggest that pericentromeric hypomethylation leads to an upregulation of DNA-damage associated transcripts. Further, we suggest that ICF- mutant zebrafish exhibit greater levels of DNA damage and DNA damage susceptibility as evidenced by γH2AX and RNA:DNA hybrids. Lastly, we suggest a loss of cdca7 acts to increase death in cdca7-/- p53-/- zebrafish.