Abstract
Histone modifications regulate gene expression and chromosomal events, yet how histone-modifying enzymes are targeted is poorly understood. Here we report that a conserved DNA repair protein, SMRC-1, associates with MET-2, the C. elegans histone methyltransferase responsible for H3K9me1 and me2 deposition. We used molecular, genetic, and biochemical methods to investigate the biological role of SMRC-1 and to explore its relationship with MET-2. SMRC-1, like its mammalian ortholog SMARCAL1, provides protection from DNA replication stress. SMRC-1 limits accumulation of DNA damage and promotes germline and embryonic viability. MET-2 and SMRC-1 localize to mitotic and meiotic germline nuclei, and SMRC-1 promotes an increase in MET-2 abundance in mitotic germline nuclei upon replication stress. In the absence of SMRC-1, germline H3K9me2 generally decreases after multiple generations at high culture temperature. Genetic data are consistent with MET-2 and SMRC-1 functioning together to limit replication stress in the germ line and in parallel to promote other germline processes. We hypothesize that loss of SMRC-1 activity causes chronic replication stress, in part because of insufficient recruitment of MET-2 to nuclei.
Highlights
Repetitive sequences pose challenges to genome integrity during DNA replication, DNA repair, and transcription
Focusing on the tissue responsible for production of sperm and eggs, the germ line, we find that SMRC-1 protects cells from DNA replication stress and promotes the accumulation of nuclear MET-2
We propose that histone modifications are regulated to promote DNA replication and DNA repair
Summary
Repetitive sequences pose challenges to genome integrity during DNA replication, DNA repair, and transcription. Repetitive genomic regions typically adopt a condensed chromatin structure that is thought to limit potentially harmful consequences of repetitive sequences by limiting transcription, stabilizing DNA to promote correct repair of DNA breaks, and limiting formation of secondary structures that would otherwise impede DNA replication [1,2,3,4]. Inappropriate transcription of repetitive regions leads to DNA:RNA hybrids (R-loops), which can prevent replication fork progression. Beyond regulation at repetitive sequences, replication and chromatin state are interdependent throughout the genome, e.g., chromatin compaction influences replication fork progression [9], and impaired replication can affect chromatin modification status and reduce the accuracy of histone incorporation at sites across the genome [10, 11]. The interplay among histone modifications, DNA replication, and repetitive sequences is complex
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