Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Sci Adv. 2024 Aug 23;10(34):eadr0036. doi: 10.1126/sciadv.adr0036.
, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout the genome. At S phase, CDCA7, but not ICF mutants, is concentrated in constitutive heterochromatin foci, and the formation of such foci can be inhibited by exogenous hemi-methylated non-B DNA bound by the CRD. Binding of the non-B DNA formed in juxtacentromeric regions during DNA replication provides a mechanism by which CDCA7 controls the specificity of DNA methylation.
编码一个羧基末端富含半胱氨酸结构域（CRD）的蛋白的 CDCA7 基因突变与免疫缺陷、着丝粒不稳定和面部异常（ICF）综合征有关，该疾病与着丝粒卫星 DNA 的低甲基化有关。CDCA7 如何将 DNA 甲基化导向着丝粒区域尚不清楚。在这里，我们表明 CDCA7 的 CRD 采用了一种独特的锌结合结构，该结构可识别由两个序列基序形成的非 B DNA 中的 CpG 二联体。CDCA7 而不是 ICF 突变体，优先结合具有链特异性 CpG 半甲基化的非 B DNA。未甲基化的序列基序在人类染色体的着丝粒处高度富集，而甲基化的基序则分布在整个基因组中。在 S 期，CDCA7 而不是 ICF 突变体，集中在组成型异染色质焦点中，并且可以通过 CRD 结合的外源半甲基化非 B DNA 抑制这种焦点的形成。在 DNA 复制过程中形成的近着丝粒区域中非 B DNA 的结合提供了一种机制，通过该机制 CDCA7 控制 DNA 甲基化的特异性。
