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bioRxiv · 10.1101/265876

Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 are required for maintaining histone methylation levels and interact with the histone demethylase LSD1/SPR-5 in C. elegans

Kim, H.-M.·Beese-Sims, S. E.·Colaiacovo, M. P.
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Abstract

The histone demethylase LSD1 was originally discovered as removing methyl groups from di- and monomethylated histone H3 lysine 4 (H3K4me2/1), and several studies suggest it plays roles in meiosis as well as epigenetic sterility given that in its absence there is evidence of a progressive accumulation of H3K4me2 through generations. In addition to transgenerational sterility, growing evidence for the importance of histone methylation in the regulation of DNA damage repair has attracted more attention to the field in recent years. However, we are still far from understanding the mechanisms by which histone methylation is involved in DNA damage repair and only a few studies have been focused on the roles of histone demethylases in germline maintenance. Here, we show that the histone demethylase LSD1/CeSPR-5 is interacting with the Fanconi Anemia (FA) protein FANCM/CeFNCM-1 based on biochemical, cytological and genetic analyses. LSD1/CeSPR-5 is required for replication stress-induced S-phase checkpoint activation and its absence suppresses the embryonic lethality and larval arrest observed in fncm-1 mutants. FANCM/CeFNCM-1 re-localizes upon hydroxyurea exposure and co-localizes with FANCD2/CeFCD-2 and LSD1/CeSPR-5 suggesting coordination between this histone demethylase and FA components to resolve replication stress. Surprisingly, the FA pathway is required for H3K4me2 maintenance regardless of the presence of replication stress. Our study reveals a connection between Fanconi Anemia and epigenetic maintenance, therefore providing new mechanistic insight into the regulation of histone methylation in DNA repair.

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Kim, H.-M., Beese-Sims, S. E., Colaiacovo, M. P.. 2018-02-14. Fanconi Anemia FANCM/FNCM-1 and FANCD2/FCD-2 are required for maintaining histone methylation levels and interact with the histone demethylase LSD1/SPR-5 in C. elegans. https://doi.org/10.1101/265876

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