Abstract
5-hydroxymethylcytosine (5hmC) is a DNA base created during active DNA demethylation by the recently discovered TET enzymes. 5hmC has essential roles in gene expression and differentiation. Here, we demonstrate that 5hmC also localizes to sites of DNA damage and repair. 5hmC accumulates at damage foci induced by aphidicolin and microirradiation and colocalizes with major DNA damage response proteins 53BP1 and γH2AX, revealing 5hmC as an epigenetic marker of DNA damage. Deficiency for the TET enzymes eliminates damage-induced 5hmC accumulation and elicits chromosome segregation defects in response to replication stress. Our results indicate that the TET enzymes and 5hmC play essential roles in ensuring genome integrity.
Highlights
Covalent modification of DNA is an essential aspect of genome function
Our finding that 5hmC is deposited locally at sites of DNA damage, combined with the results showing that TET enzymes aid in preventing damage-induced chromosome missegregation, strongly suggests an important role for 5hmC in promoting DNA repair and genome integrity
Consistent with this hypothesis, we observed reduced DAPI intensity, indicative of chromatin decompaction, at 5hmC foci induced in response to DNA damage (Figure S2A)
Summary
Georgia Rose Kafer, Xuan Li, Takuro Horii, Isao Suetake, Shoji Tajima, Izuho Hatada, Peter Mark Carlton. Kafer et al demonstrate that DNA damage causes the modified DNA base 5-hydroxymethylcytosine (5hmC) to become locally enriched over broad chromosomal domains and that the TET enzymes promote correct chromosome segregation during replication stress. Highlights d 5hmC is actively enriched at endogenous DNA damage sites in cancer cell lines.
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