Use of JULGI for diagnosing or treating G-quadruplex related diseases

본 발명은 JULGI의 구아닌-사중합체 관련 질환의 진단 및 치료 용도에 관한 것으로, 보다 구체적으로는 JULGI 단백질 또는 상기 단백질과 80% 이상의 상동성을 갖는 단백질을 포함하는, 구아닌-사중합체(G-quadruplex) 검출용 조성물, 상기 검출용 조성물을 포함하는 진단용 조성물 및 상기 진단용 조성물을 포함하는 진단 키트, 구아닌-사중합체와 병리적 상관관계를 가지는 퇴행성 신경질환, 암 또는 바이러스 감염 질환의 진단을 위한 정보제공방법, JULGI 단백질 또는 상기 단백질과 80% 이상의 상동성을 갖는 단백질, 또는 이의 돌연변이 단백질을 포함하는 퇴행성 신경질환, 암, 또는 바이러스 감염질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 따른 JULGI은 G-quadruplex 구조에 결합하는 활성에 기인하여 G-quadruplex 구조의 비정상적인 형성 및 해리와 병리학적인 상관관계를 가지는 다양한 질환의 진단 또는 치료에 유용하게 이용될 수 있을 것으로 기대된다

HCR1 restricts the number of meiotic crossovers in Arabidopsis

Meiotic crossovers are tightly restricted in most eukaryotes, despite an excess of initiating DNA double-strand breaks. The majority of plant crossovers are dependent on Class I interfering repair, with a minority formed via the Class II pathway. Class II repair is limited by anti-recombination pathways, however similar pathways repressing Class I crossovers are unknown. We performed a forward genetic screen in Arabidopsis using fluorescent crossover reporters, to identify mutants with increased or decreased recombination frequency. We identified HIGH CROSSOVER RATE1 (HCR1) as repressing crossovers and encoding PROTEIN PHOSPHATASE X1. Genome-wide analysis showed that hcr1 crossovers are increased in the distal chromosome arms. MLH1 foci significantly increase in hcr1 and crossover interference decreases, consistent with a major effect on Class I repair. Yeast two-hybrid and in planta assays demonstrate interaction between HCR1 and Class I proteins, including HEI10, PTD, and MSH5. We propose that HCR1 acts in opposition to pro-recombination kinases to limit crossover numbers in Arabidopsis.1

HCR2 limits crossovers by repressing HEI10 transcription in Arabidopsis

Meiotic crossover creates new genetic variations and is produced by the repair of programmed DSBs (DNA double strand break sites). Despite excessive meiotic DSBs, crossover number is limited along each pair of homologous chromosomes. The majority of crossovers are interfering and formed by crossover-promoting ZMM proteins including HEI10, a dosage dependent E3 ligase. However, molecular mechanisms restricting number of interfering crossovers remain unexplored. We here identified HCR2 (HIGH CROSSOVER RATE 2) via a forward genetic screen using fluorescent reporter in Arabidopsis. Using genome wide crossover mapping and fluorescent reporter systems we found that the hcr2 and meiosis specific HCR2 knockdown plants display elevated crossover frequency in chromosome arms, with reduced crossover interference. The hcr2 mutation lead to increase the transcript level of HEI10, thereby elevating crossover number. Our data reveal a novel mechanism of limiting crossovers by which HCR2 transcription regulator represses HEI10 transcription.1

HIGH CROSSOVER RATE1 encodes PROTEIN PHOSPHATASE X1 and restricts meiotic crossovers in Arabidopsis

Meiotic crossovers are tightly restricted in most eukaryotes, despite an excess of initiating DNA double-strand breaks. The majority of plant crossovers are dependent on Class I interfering repair, with a minority formed via the Class II pathway. Class II repair is limited by anti-recombination pathways, however similar pathways repressing Class I crossovers are unknown. We performed a forward genetic screen in Arabidopsis using fluorescent crossover reporters, to identify mutants with increased or decreased recombination frequency. We identified HIGH CROSSOVER RATE1 (HCR1) as repressing crossovers and encoding PROTEIN PHOSPHATASE X1. Genome-wide analysis showed that hcr1 crossovers are increased in the distal chromosome arms. MLH1 foci significantly increase in hcr1 and crossover interference decreases, consistent with a major effect on Class I repair. Yeast two-hybrid and in planta assays demonstrate interaction between HCR1 and Class I proteins, including HEI10, PTD, and MSH5. We propose that HCR1 acts in opposition to pro-recombination kinases to limit crossover numbers in Arabidopsis.1

HIGH CROSSOVER RATE1 restricts the number of meiotic crossovers in Arabidopsis

Meiotic crossover creates new combinations of genetic variation and ensures balanced chromosome transmission. Crossover numbers per meiosis are tightly restricted in most eukaryotes, despite a large excess of initiating DNA double-strand break precursors. The majority of crossovers in plants are dependent on the Class I interfering repair pathway. A minority of crossovers are formed by the Class II non-interfering pathway, which is normally limited by multiple anti-recombination pathways. However, similar pathways that limit Class I interfering crossovers are unknown. To identify regulators of crossover formation, we performed a forward genetic screen in Arabidopsis using fluorescent crossover reporters, to identify mutants with increased or decreased recombination frequency. This screen identified the HIGH CROSSOVER RATE1 (HCR1) gene as repressing crossovers. Using genome-wide analysis we show that hcr1 crossovers are most strongly increased in the distal euchromatic chromosome arms. We observe a significant increase in MLH1 foci in hcr1 and a decrease in the strength of crossover interference, which is consistent with a major effect on the Class I pathway. We used yeast two hybrid and in planta assays to demonstrate physical interaction between HCR1 and multiple proteins within the Class I interfering pathway, including HEI10, PTD, and MSH5. Our data identify HCR1 as limiting the number of interfering Class I crossovers in plants. We propose that HCR1 acts in opposition to pro-recombination DNA repair or cell division kinases, in order to limit crossover number per meiosis.1