RNF8-dependent histone ubiquitination during DNA damage response and spermatogenesis

Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Acta Biochimica et Biophysica Sinica (Impact Factor: 2.19). 03/2011; 43(5):339-45. DOI: 10.1093/abbs/gmr016
Source: PubMed

ABSTRACT Histone ubiquitination regulates the chromatin structure that is important for many biological processes. Recently, ubiquitination of histones was observed during the DNA damage response (DDR), and this modification is controlled by really interesting new gene (RING) domain E3 ligase, RNF8. Together with the E2 conjugating enzyme UBC13, RNF8 catalyzes ubiquitination of the histones H2A and H2AX during the DDR, thus facilitating downstream recruitment of DDR factors, such as p53 binding protein 1 (53BP1) and breast cancer type 1 susceptibility protein (BRCA1), to the damage site. Accordingly, the RNF8 knockout mice display phenotypes associated with failed DDR, including hypersensitivity to ionizing radiation, V(D)J recombination deficiency, and a predisposition to cancer. In addition to the DDR phenotypes, RNF8 knockout mice fail to generate mature sperm during spermatogenesis, resulting in male sterility. The RNF8 knockout mice also have a drastic reduction in histone ubiquitination in the testes. These findings indicate that the role of histone ubiquitination during chromatin remodeling in two different biological events could be linked by an RNF8-dependent mechanism. Here, we review the molecular mechanism of RNF8-dependent histone ubiquitination both in DDR and spermatogenesis.

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    • "Interestingly, mutant spermatocytes deficient for E3 ligase RNF8 show normal MSCI and meiotic progression despite the absence of ubiH2A and ubiquitin conjugates in the sex body (Lu et al., 2010; Ma et al., 2011). Histone modifications show dynamic spatiotemporal patterns during prophase I, suggesting an important role during meiosis. "
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    ABSTRACT: Meiosis is one of the most critical developmental processes in sexually reproducing organisms. One round of DNA replication followed by two rounds of cell divisions results in generation of haploid gametes (sperm and eggs in mammals). Meiotic failure typically leads to infertility in mammals. In the process of meiotic recombination, maternal and paternal genomes are shuffled, creating new allelic combinations and thus genetic variety. However, in order to achieve this, meiotic cells must self-inflict DNA damage in the form of programmed double-strand breaks (DSBs). Complex processes evolved to ensure proper DSB repair, and to do so in a way that favors interhomolog reciprocal recombination and crossovers. The hallmark of meiosis, a structurally conserved proteinaceous structure called the synaptonemal complex, is found only in meiotic cells. Conversely, meiotic homologous recombination is an adaptation of the mitotic DNA repair process but involving specialized proteins. In this chapter, we summarize current developments in mammalian meiosis enabled by genetically modified mice.
    International review of cell and molecular biology 08/2012; 298:179-227. DOI:10.1016/B978-0-12-394309-5.00005-5 · 3.42 Impact Factor
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    • "GRTH associated mRNA messages of histone cluster 1, H2AB/H2AE also link to ubiquitin-like modifier activating enzyme 1 (UBA1) and further extend to the ubiquin network signaling (Fig. 1A, Nt.1). Because of the essential role of histone ubiquitination in the chromatin remodeling to permit transition proteins /protamines replacement leading to final mature germ cell production [21], [22], [23], this GRTH-histone-ubiquitin network offers an additional regulatory route of GRTH action to be explored during spermatogenesis. "
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    ABSTRACT: Gonadotropin Regulated Testicular RNA Helicase (GRTH/Ddx25) is a testis-specific multifunctional RNA helicase and an essential post-transcriptional regulator of spermatogenesis. GRTH transports relevant mRNAs from nucleus to cytoplasmic sites of meiotic and haploid germ cells and associates with actively translating polyribosomes. It is also a negative regulator of steroidogenesis in Leydig cells. To obtain a genome-wide perspective of GRTH regulated genes, in particularly those associated with polyribosomes, microarray differential gene expression analysis was performed using polysome-bound RNA isolated from testes of wild type (WT) and GRTH KO mice. 792 genes among the entire mouse genome were found to be polysomal GRTH-linked in WT. Among these 186 were down-regulated and 7 up-regulated genes in GRTH null mice. A similar analysis was performed using total RNA extracted from purified germ cell populations to address GRTH action in individual target cells. The down-regulation of known genes concerned with spermatogenesis at polysomal sites in GRTH KO and their association with GRTH in WT coupled with early findings of minor or unchanged total mRNAs and abolition of their protein expression in KO underscore the relevance of GRTH in translation. Ingenuity pathway analysis predicted association of GRTH bound polysome genes with the ubiquitin-proteasome-heat shock protein signaling network pathway and NFκB/TP53/TGFB1 signaling networks were derived from the differentially expressed gene analysis. This study has revealed known and unexplored factors in the genome and regulatory pathways underlying GRTH action in male reproduction.
    PLoS ONE 03/2012; 7(3):e32470. DOI:10.1371/journal.pone.0032470 · 3.23 Impact Factor
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    ABSTRACT: Protein ubiquitination plays an important role in activating the DNA damage response and maintaining genomic stability. In response to DNA double-strand breaks (DSBs), a ubiquitination cascade occurs at DNA lesions. Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). At DSBs, CHFR regulates the first wave of protein ubiquitination. Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Thus, these results demonstrate that CHFR is an important E3 ligase in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation.
    Nucleic Acids Research 12/2012; 41(3). DOI:10.1093/nar/gks1278 · 9.11 Impact Factor
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