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ADP-ribosylation of histone variant H2AX promotes base excision repair

ABSTRACT: Optimal DNA damage response is associated with ADP-ribosylation of histones. However, the underlying molecular mechanism of DNA damage-induced histone ADP-ribosylation remains elusive. Herein, using unbiased mass spectrometry, we identify that glutamate residue 141 (E141) of variant histone H2AX is ADP-ribosylated following oxidative DNA damage. In-depth studies performed with wild-type H2AX and the ADP-ribosylation-deficient E141A mutant suggest that H2AX ADP-ribosylation plays a critical role in base excision repair (BER). Mechanistically, ADP-ribosylation on E141 mediates the recruitment of Neil3 glycosylase to the sites of DNA damage for BER. Moreover, loss of this ADP-ribosylation enhances serine-139 phosphorylation of H2AX (?H2AX) upon oxidative DNA damage, and erroneously causes the accumulation of DNA double-strand break (DSB) response factors. Taken together, these results reveal that H2AX ADP-ribosylation not only facilitates BER repair, but also suppresses the ?H2AX-mediated DSB response.

SUBMITTER: Dr. Qian Chen

PROVIDER: S-SCDT-EMBOJ-2020-104542 | biostudies-other |

REPOSITORIES: biostudies-other

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ADP-ribosylation of histone variant H2AX promotes base excision repair.

Project description:Optimal DNA damage response is associated with ADP-ribosylation of histones. However, the underlying molecular mechanism of DNA damage-induced histone ADP-ribosylation remains elusive. Herein, using unbiased mass spectrometry, we identify that glutamate residue 141 (E141) of variant histone H2AX is ADP-ribosylated following oxidative DNA damage. In-depth studies performed with wild-type H2AX and the ADP-ribosylation-deficient E141A mutant suggest that H2AX ADP-ribosylation plays a critical role in base excision repair (BER). Mechanistically, ADP-ribosylation on E141 mediates the recruitment of Neil3 glycosylase to the sites of DNA damage for BER. Moreover, loss of this ADP-ribosylation enhances serine-139 phosphorylation of H2AX (γH2AX) upon oxidative DNA damage and erroneously causes the accumulation of DNA double-strand break (DSB) response factors. Taken together, these results reveal that H2AX ADP-ribosylation not only facilitates BER repair, but also suppresses the γH2AX-mediated DSB response.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:The A-type lamins (lamin A/C), encoded by the Lmna gene, are important structural components of the nuclear lamina. Lmna mutations lead to degenerative disorders, including the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells. The mechanism involves impairment of the APE1 and POLβ enzyme activities in BER. Also, Lmna null mouse fibroblasts displayed reduced expression of several core BER enzymes (PARP1, LIG3, and POLβ). Moreover, the robustness of APE1 and POLβ activities and the rate of BER were enhanced by lamin A/C-augmented poly(ADP-ribose) polymer formation (PARylation). Finally, we report that HGPS fibroblasts are defective in BER. Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for human cancer and aging.

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