Abstract
SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers.
Highlights
HR occurs predominantly at S and G2 phases when a sister chromatid is accessible[2]
To explore additional and novel roles of SMYD3 in biological processes, we analysed our previously conducted whole-genome microarray data of RNAs isolated from shLuc vs. shSMYD3 MCF7 cells (GEO accession number GSE58048), in which a lentivirus shRNA infection system was used for stable knockdown of SMYD326. 449 genes were downregulated upon SMYD3 knockdown
The gene ontology (GO) analysis indicated that these genes were mainly involved in cell cycle, DNA metabolic process, response to DNA damage stimulus, cell proliferation and macromolecular complex subunit organization (Fig. 1a)
Summary
HR occurs predominantly at S and G2 phases when a sister chromatid is accessible[2]. The repair is initiated by a resection process, which includes MRE11-RAD50-NBS1 (MRN) end sensing complex, CtIP endonuclease[3], EXO1 exonuclease[4], and BLM helicase[5], to remove oligonucleotides from each side of the DSB and expose single-stranded DNA (ssDNA) tails for forming RAD51-ssDNA filaments with the help of BRCA26. During C-NHEJ, cells utilise Ku70/Ku80 heterodimer and DNA-dependent protein kinase (DNA-PK) to recognize and ligate DSB ends via little (less than ten base pairs) or no homology between the joined ends, which is, an error-prone pathway[9, 10]. Cancer development is closely related to aberrant histone modification which causes abnormal genes expression. SMYD3 regulates gene transcription through methylating histones, including H2.A.ZK101me[226], H3K4me2/327, H4K20me2/328, and H4K5me1/2/329. SMYD3 modifies non-histone proteins VEGFR and MAP3K2 to promote metastasis[32] and Ras/Raf/MEK/ERK signaling[33] in cancer development, respectively. SMYD3 knockdown leads to decreased methylation of H3K4 and recruitment of RNA polymerase II (RNAPII) at the target gene promoters. These data reveal that SMYD3 maintains genome stability by ensuring normal expression levels of HR repair proteins
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