Academic journal article Genetics

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 Caenorhabditis Elegans

Academic journal article Genetics

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 Caenorhabditis Elegans

Article excerpt

MOST eukaryotes package their DNA around histones and form nucleosomes to compact the genome. A nucleosome is the basic subunit of chromatin and comprises ~147 bp of DNA wrapped around a protein octamer which consists of two molecules each of four highly conserved core histones: H2A, H2B, H3, and H4. Core histones can be replaced by various histone variants, each of which is associated with dedicated functions such as packaging the genome, gene regulation, DNA repair, and meiotic recombination (Talbert and Henikoff 2010). Both the N- and C-terminal tails of core histones are subjected to various types of posttranslational modifications including acetylation, methylation, SUMOylation, phosphorylation, ubiquitination, ADP-ribosylation, and biotinylation.

Histone demethylases have been linked to a wide range of human carcinomas (Pedersen and Helin 2010). Dynamic histone methylation patterns influence DNA double-strand break (DSB) formation and DNA repair, meiotic crossover events, and transcription levels (Zhang and Reinberg 2001; Clément and de Massy 2017). However, the mechanisms by which histone-modifying enzymes coordinate their efforts to signal for the desired outcome are not well understood, and even less is known about the role of histone demethylases in promoting germline maintenance.

The mammalian histone demethylase LSD1 was originally discovered as a di- and monomethylated histone H3 lysine 4 (H3K4me2/1)-specificdemethylase (Shietai. 2004). Studies in flies and fission yeast revealed increased sterility in the absence of LSD1; however, the underlying mechanism of function by which LSD1 promotes fertility remained elusive (Di Stefano et ai. 2007; Lan et ai. 2007; Rudolph et al. 2007). Caenorhabditis elegans studies suggested that it plays a role in meiosis, and LSD1/CeSPR-5 mutant analysis revealed a progressive sterility accompanied by a progressive accumulation of H3K4me2 on a subset of genes, including spermatogenesis genes (Katz et al. 2009). In addition to transgenerational sterility, our previous studies discovered that this histone demethylase is important for DSB repair (DSBR) as well as p53-dependent germ cell apoptosis in the C. elegans germline (Nottke et al. 2011), linking H3K4me2 modulation via SPR-5 to proper repair of meiotic DSBs for the first time. Other studies supporting the importance of histone methylation in the regulation of DNA damage repair have attracted more attention to the field in recent years (Huang et al. 2007; Katz et al. 2009; Black et al. 2010; Mosammaparast et al. 2013; Peng et al. 2015). However, the mechanisms by which histone demethylation is involved in DNA damage repair remain unclear and only a few studies have been focused on its roles in germline maintenance.

A growing body of work supports a role for components from the Fanconi anemia (FA) pathway in response to DNA replication-fork arrest and interstrand cross-link (ICL) repair (Adamo et al. 2010; Schlacher et al. 2012; Raghunandan et al. 2015; Lachaud et al. 2016). FANCM guides the FA core complex to DNA lesions and displays a strong preference for binding branched DNA structures, such as replication forks, in vitro (Gari et al. 2008). The FA core complex monoubiquitinates a heterodimer of FANCD2/FANCI at ICL-induced stalled replication forks, which in turn recruits and activates downstream FA proteins and participates with BRCA1 and RAD51 in repair during S phase (Taniguchi et al. 2002; Xue et al. 2008). C. elegans FA proteins-FNCM-1, FCD-2, and FNCI-1-are required for ICL repair (Lee et al. 2010), however their function remains to be investigated for DSBR.

Here, we show that the histone demethylase LSD1/CeSPR-5 interacts with the FA FANCM/CeFNCM-1 protein using biochemical, cytological, and genetic analyses. LSD1/CeSPR-5 is required for hydroxyurea (HU) -induced S phase DNA damage checkpoint activation, and its absence suppresses the embryonic lethality and larval arrest displayed infncm-1 mutants. …

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