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      • Species specificity of human RPA in simian virus 40 DNA replication lies in T-antigen-dependent RNA primer synthesis

        Wang, Mu,Park, Jang-Su,Ishiai, Masamichi,Hurwitz, Jerard,Lee, Suk-Hee 부산대학교 유전공학연구소 2000 분자생물학 연구보 Vol.16 No.-

        Replication protein A (RPA) is a three-subunit protein complex with multiple functions in DNA replication. Previous study indicated that human RPA (h-RPA) could not be replaced by Schizosaccharomyces pombe RPA (sp-RPA) in simian virus 40 (SV40) replication, suggesting that h-RPA may have a specific function in SV40 DNA replication, we prepared heterologous RPAs containing the mixture of human and S. pombe subunits and compared these preparations for various enzmatic activities. Heterologous RPAs containing two human subunits supported SV40 DNA replication, whereas those containing only one human subunit poorly supported DNA replication, suggesting that RPA complex requires at least two human subunits to support its function in SV40 DNA replication. All heterologous RPAs effectively supported single-stranded(ss)DNA binding activity and an elongation of a primed DNa template catalyzed by DNA polymerase(pol) α and δ. A strong correlation between SV40 DNA replication activity and primer synthesis by pol α-primase complex was observed among the heterologous RPAs. Furthermore, T-ag showed a strong interaction with 70- and 34-kDa subunits from human, but poorly interacted with their S.pombe counterparts, indicating that the specificity of h-RPA is due to its role in RNa primer synthesis. In the SV40 replication reaction, the addition of increasing amounts of sp-RPA in the presence of fixed amount of h-RPA significantly reduced overall DNA synthesis, but increased the size of lagging strand, supporting a specific role for h-RPA in RNA primer synthesis. Together, these results suggest that the specificity of h-RPA in SV40 replication lies in T-ag-dependent RNA primer synthesis.

      • Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian <i>Atad5</i>

        Bell, Daphne W.,Sikdar, Nilabja,Lee, Kyoo-young,Price, Jessica C.,Chatterjee, Raghunath,Park, Hee-Dong,Fox, Jennifer,Ishiai, Masamichi,Rudd, Meghan L.,Pollock, Lana M.,Fogoros, Sarah K.,Mohamed, Hassa Public Library of Science 2011 PLoS genetics Vol.7 No.8

        <▼1><P>ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals <I>in vivo</I>. To test this hypothesis, we generated heterozygous (<I>Atad5<SUP>+/m</SUP></I>) mice that were haploinsuffficient for Atad5. <I>Atad5<SUP>+/m</SUP></I> mice displayed high levels of genomic instability <I>in vivo</I>, and <I>Atad5<SUP>+/m</SUP></I> mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient <I>Atad5<SUP>+/m</SUP></I> mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the <I>Atad5<SUP>+/m</SUP></I> mice. Consistent with a role for <I>Atad5</I> in suppressing tumorigenesis, we also identified somatic mutations of <I>ATAD5</I> in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian <I>Atad5</I> are sufficient to cause genomic instability and tumorigenesis.</P></▼1><▼2><P><B>Author Summary</B></P><P>Genomic instability is a hallmark of tumorigenesis, suggesting that mutations in genes suppressing genomic instability contribute to this phenotype. In this study, we demonstrate for the first time that haploinsufficiency for Atad5, a protein that is important in stabilizing stalled DNA replication forks by regulating PCNA ubiquitination during DNA damage bypass, predisposes >90% of mice to tumorigenesis in multiple organs. In heterozygous <I>Atad5</I> mice, both somatic cells and the spontaneous tumors showed high levels of genomic instability. In a subset of sporadic human endometrial tumors, we identified heterozygous loss-of-function somatic mutations in the <I>ATAD5</I> gene, consistent with the role of mouse <I>Atad5</I> in suppressing tumorigenesis. Collectively, our findings suggest that <I>ATAD5</I> may be a novel tumor suppressor gene.</P></▼2>

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