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Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases.

ABSTRACT: The methyltransferase DOT1L methylates histone H3 at K79 to facilitate specific biological events. H3K79 dimethylation (H3K79-2Me) by DOT1L influences the DNA damage response by promoting 53BP1 recruitment to DNA damage sites; however, it is unclear if this methylation is required as 53BP1 interacts with dimethylated H4 (H4K20-2Me) with a much higher affinity. We demonstrate that H3K79-2Me, while negligible during S-phase, is required for ionizing radiation (IR)-induced 53BP1 foci formation during G1/G2-phases when H4K20-2Me levels are low. Further, we describe an essential role for HLA-B-associated transcript 3 (Bat3) in regulating this process in U2OS cells. Bat3 co-localizes with DOT1L at histone H3, and Bat3 knockdown results in decreased DOT1L-H3 interaction and H3K79-2Me, leading to a reduction in IR-induced 53BP1 foci formation, defects in DNA repair and increased sensitivity to IR. We demonstrate that a conserved Bat3 ubiquitin-like motif and a conserved DOT1L ubiquitin-interacting motif promote DOT1L-Bat3 interaction to facilitate efficient H3K79-2Me and IR-induced 53BP1 foci formation during G1/G2-phases. Taken together, our findings identify a novel role for Bat3 in regulating DOT1L function, which plays a critical role in DNA damage response.

SUBMITTER: Wakeman TP

PROVIDER: S-EPMC3343460 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases.

Wakeman Timothy P TP Wang Qinhong Q Feng Junjie J Wang Xiao-Fan XF

The EMBO journal 20120228 9

The methyltransferase DOT1L methylates histone H3 at K79 to facilitate specific biological events. H3K79 dimethylation (H3K79-2Me) by DOT1L influences the DNA damage response by promoting 53BP1 recruitment to DNA damage sites; however, it is unclear if this methylation is required as 53BP1 interacts with dimethylated H4 (H4K20-2Me) with a much higher affinity. We demonstrate that H3K79-2Me, while negligible during S-phase, is required for ionizing radiation (IR)-induced 53BP1 foci formation duri ...[more]

PMID: 22373577

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Project description:BackgroundMajor genomic surveillance mechanisms regulated in response to DNA damage exist at the G1/S and G2/M checkpoints. It is presumed that these delays provide time for the repair of damaged DNA. Cells have developed multiple DNA repair pathways to protect themselves from different types of DNA damage. Oxidative DNA damage is processed by the base excision repair (BER) pathway. Little is known about the BER of ionizing radiation-induced DNA damage and putative heterogeneity of BER in the cell cycle context. We measured the activities of three BER enzymes throughout the cell cycle to investigate the cell cycle-specific repair of ionizing radiation-induced DNA damage. We further examined BER activities in G2 arrested human cells after exposure to ionizing radiation.ResultsUsing an in vitro incision assay involving radiolabeled oligonucleotides with specific DNA lesions, we examined the activities of several BER enzymes in the whole cell extracts prepared from synchronized human HeLa cells irradiated in G1 and G2 phase of the cell cycle. The activities of human endonuclease III (hNTH1), a glycosylase/lyase that removes several damaged bases from DNA including dihydrouracil (DHU), 8-oxoguanine-DNA glycosylase (hOGG1) that recognizes 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG) lesion and apurinic/apyrimidinic endonuclease (hAPE1) that acts on abasic sites including synthetic analog furan were examined.ConclusionOverall the repair activities of hNTH1 and hAPE1 were higher in the G1 compared to G2 phase of the cell cycle. The percent cleavages of oligonucleotide substrate with furan were greater than substrate with DHU in both G1 and G2 phases. The irradiation of cells enhanced the cleavage of substrates with furan and DHU only in G1 phase. The activity of hOGG1 was much lower and did not vary within the cell cycle. These results demonstrate the cell cycle phase dependence on the BER of ionizing radiation-induced DNA damage. Interestingly no evidence of enhanced BER activities was found in irradiated cells arrested in G2 phase.

Dataset Information

Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases.

Publications

Bat3 facilitates H3K79 dimethylation by DOT1L and promotes DNA damage-induced 53BP1 foci at G1/G2 cell-cycle phases.

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