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第33回生体物質化学セミナーを開催します(2/16)【生命分子化学科】

[2018年2月13日]

第33回 生体物質化学セミナーのご案内

生体物質化学研究室では、各方面で活躍している研究者の方々を講師として招いた「生体物質化学セミナー」を開催しています。学内にいながら最先端の研究に触れることが出来る機会です。学年、分野を問わず、広く公開いたしますので、皆様ご参加ください。

【第33回 生体物質化学セミナーのご案内】
日 時  2月16日(金)16:00 〜
場 所  稲盛記念会館 105講義室
テーマ  『The role of RNase H2 in genome integrity』
講 師  上原 了 先生  (Division of Intramural Research, NIH)  
対 象  学生、院生、教職員

<概要>
RNase H2 has two distinct functions: removal of ribonucleotides (rNMPs) incorporated during DNA replication and resolution of R-loop structures formed during transcription. DNA polymerases are far from perfect to discriminate dNTPs from rNTPs and therefore incorporate rNMPs into genomic DNA every 7,000 nucleotides, resulting in an accumulation of more than 1,000,000 rNMPs in mouse DNA in the absence of RNase H2 (Rejins, et al. 2012). The highly efficient Ribonucleotide Excision Repair (RER) is initiated by cleaving at the rNMPs by RNase H2 followed by repair synthesis to replace rNMPs with dNMPs. R-loops, which is composed of RNA/DNA hybrid and displaced single-stranded DNA, are formed by invasion of transcribed RNA strand into dsDNA. RNase H2 as well as RNase H1 efficiently removes R-loops by degrading RNA strand of RNA/DNA hybrid. Both substrates of RNase H2 are responsible for chromosomal instability if persistent but the dual function of RNase H2 makes it difficult to assign the phenotype to defects in RER or R-loop degradation. We modified RNase H2 catalytic subunit to almost eliminate RER activity but fully retaining RNA/DNA hydrolysis activity. The Ribonucleotide Excision-Defective (RED) RNase H2 mutant (RNase H2RED) revealed that an accumulation of rNMPs in mouse DNA solely leads to early embryonic lethality as reported for Rnaseh2b- and Rnaseh2c-null mice. In contrast, a human disorder (AGS)-related RNase H2 mutant with reduced RER activity develops to birth. Estimation of rNMPs in RED and AGS-related mutants defines rNMPs threshold above which p53 induces apoptosis. These two mutants compete for rNMPs substrate on genomic DNA, preventing each RNase H2 to be fully active. This suggests AGS patient with compound heterozygous mutations may not necessarily reflect the properties of proteins recombinantly expressed and characterized in vitro. We further obtained another RNase H2 mutant that is defective in RNA/DNA hydrolysis. Future studies with Hybrid-defective (HD) mutant may allow us to assign any phenotype in RNase H2-defective organism to loss of each activity.

第33回生体物質化学セミナー

第33回生体物質化学セミナー

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