Meiosis is a specialized cell division for producing haploid gametes in sexually reproducing organisms.In this study,we have independently identified a novel meiosis protein male meiosis recombination regulator(MAMERR...Meiosis is a specialized cell division for producing haploid gametes in sexually reproducing organisms.In this study,we have independently identified a novel meiosis protein male meiosis recombination regulator(MAMERR)/4930432 K21 Rik and showed that it is indispensable for meiosis prophase I progression in male mice.Using super-resolution structured illumination microscopy,we found that MAMERR functions at the same double-strand breaks as the replication protein A and meiosis-specific with OB domains/spermatogenesis associated 22 complex.We generated a Mamerr-deficient mouse model by deleting exons 3 e6 and found that most of Mamerrà/àspermatocytes were arrested at pachynema and failed to progress to diplonema,although they exhibited almost intact synapsis and progression to the pachytene stage along with XY body formation.Further mechanistic studies revealed that the recruitment of DMC1/RAD51 and heat shock factor 2 ebinding protein in Mamerrà/àspermatocytes was only mildly impaired with a partial reduction in double-strand break repair,whereas a substantial reduction in ubiquitination on the autosomal axes and on the XY body appeared as a major phenotype in Mamerrà/àspermatocytes.We propose that MAMERR may participate in meiotic prophase I progression by regulating the ubiquitination of key meiotic proteins on autosomes and XY chromosomes,and in the absence of MAMERR,the repressed ubiquitination of key meiotic proteins leads to pachytene arrest and cell death.展开更多
Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,dec...Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,decorate chromatin domains surrounding DNA double-strand breaks(DSBs).Recent work implicated ubiquitylated histones in orchestrating cell cycle checkpoints,DNA repair and gene transcription.Here we summarize recent advances that contribute to our current knowledge of the highly dynamic nature of DSB-associated histone ubiquitylation,and discuss major challenges ahead in understanding the versatility of ubiquitin conjugation in maintaining genome stability.展开更多
基金supported by grants from the Hong Kong Research Grant Council(17114920,K.L.and R.H.W.L.)the University of Hong Kong(K.L.)+3 种基金the Sanming Project of Medicine in Shenzhen,China(SZSM201612083,W.S.B.Y.)High Level-Hospital Program,Health Commission of Guangdong Province,China(HKUSZH201902018,K.L.)Shenzhen-Hong Kong Innovation Circle Type D(K.L.)a grant from the NIH/NIGMS(National Institute of General Medical Sciences)R35GM118052(P.J.W.)
文摘Meiosis is a specialized cell division for producing haploid gametes in sexually reproducing organisms.In this study,we have independently identified a novel meiosis protein male meiosis recombination regulator(MAMERR)/4930432 K21 Rik and showed that it is indispensable for meiosis prophase I progression in male mice.Using super-resolution structured illumination microscopy,we found that MAMERR functions at the same double-strand breaks as the replication protein A and meiosis-specific with OB domains/spermatogenesis associated 22 complex.We generated a Mamerr-deficient mouse model by deleting exons 3 e6 and found that most of Mamerrà/àspermatocytes were arrested at pachynema and failed to progress to diplonema,although they exhibited almost intact synapsis and progression to the pachytene stage along with XY body formation.Further mechanistic studies revealed that the recruitment of DMC1/RAD51 and heat shock factor 2 ebinding protein in Mamerrà/àspermatocytes was only mildly impaired with a partial reduction in double-strand break repair,whereas a substantial reduction in ubiquitination on the autosomal axes and on the XY body appeared as a major phenotype in Mamerrà/àspermatocytes.We propose that MAMERR may participate in meiotic prophase I progression by regulating the ubiquitination of key meiotic proteins on autosomes and XY chromosomes,and in the absence of MAMERR,the repressed ubiquitination of key meiotic proteins leads to pachytene arrest and cell death.
基金supported by Faculty Development Fund and Seed Funding for Applied Research to MSYH(No.201007160001).
文摘Histone ubiquitylation has emerged as an important chromatin modification associated with DNA damage signaling and repair pathways.These histone marks,laid down by E3 ubiquitin ligases that include RNF8 and RNF168,decorate chromatin domains surrounding DNA double-strand breaks(DSBs).Recent work implicated ubiquitylated histones in orchestrating cell cycle checkpoints,DNA repair and gene transcription.Here we summarize recent advances that contribute to our current knowledge of the highly dynamic nature of DSB-associated histone ubiquitylation,and discuss major challenges ahead in understanding the versatility of ubiquitin conjugation in maintaining genome stability.
