Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair.

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair.

The Mechanism of Chromatin Remodeler SMARCAD1/Fun30 in Response to DNA Damage.

DNA packs into highly condensed chromatin to organize the genome in eukaryotes but occludes many regulatory DNA elements. Access to DNA within nucleosomes is therefore required for a variety of biological processes in cells including transcription, replication, and DNA repair. To cope with this problem, cells employ a set of specialized ATP-dependent chromatin-remodeling protein complexes to enable dynamic access to packaged DNA. In the present review, we summarize the recent advances in the functional and mechanistic studies on a particular chromatin remodeler SMARCAD1Fun30 which has been demonstrated to play a key role in distinct cellular processes and gained much attention in recent years. Focus is given to how SMARCAD1Fun30 regulates various cellular processes through its chromatin remodeling activity, and especially the regulatory role of SMARCAD1Fun30 in gene expression control, maintenance and establishment of heterochromatin, and DNA damage repair. Moreover, we review the studies on the molecular mechanism of SMARCAD1Fun30 that promotes the DNA end-resection on double-strand break ends, including the mechanisms of recruitment, activity regulation and chromatin remodeling.

The Bre1/Rad6 machinery: writing the central histone ubiquitin mark on H2B and beyond.

Mono-ubiquitination on H2B (H2Bub1) is an evolutionarily conserved histone post-translational modification implicated in various important physiological processes including DNA replication, transcription activation, and DNA damage repair. The Bre1/Rad6 ubiquitination machinery is currently considered to be the sole writer of H2Bub1, but the mechanistic basis by which it operates is unclear. Recently, the RING-type E3 ligase Bre1 was proposed to associate with the E2 enzyme Rad6 through a novel interaction between Bre1 RBD (Rad6 binding domain) and Rad6; and the RING domain of Bre1 that is responsible for the nucleosomal acidic patch binding also interacts with Rad6 to stimulate its catalytic activity. Recent discoveries have yielded evidence for the phenomenon of liquid-liquid phase separation in the context of H2Bub1, and its regulation by other histone post-translational modifications. This review summarizes current knowledge about Bre1/Rad6-mediated H2B ubiquitination, including the physiological functions and the molecular basis for writing and regulation of this central histone ubiquitin mark. Possible models for the Bre1/Rad6 machinery bound to nucleosomes bearing different modifications in the writing step are also disclosed.

Endemic situation of schistosomiasis in surveillance sites of Tianmen City from 2015 to 2018 / 中国血吸虫病防治杂志

Objective To monitor the change patterns of the endemic situation of schistosomiasis in Tianmen City from 2015 to 2018, so as to provide the evidence for formulating the schistosomiasis control strategy in the city. Methods A total of 8 schistosomiasis surveillance sites were assigned in Tianmen City from 2015 to 2018, and the endemic situation of schistosomiasis and the related epidemiological factors were monitored. Results During the period from 2015 to 2018, a total of 15 983 local person-times and 3 629 mobile populations were detected for schistosomiasis using an indirect hemagglutination test (IHA) in Tianmen City, and the sero-prevalence was 0.88% to 1.44% and 0.96% to 2.39%, respectively; however, no egg-positives were identified. A total of 1 245 herd-times were detected, and no egg-positives were found in bovines. In addition, the areas of snail habitats were 116.69 to 117.23 hm2 and the mean densities of living snails were 0.07 to 0.17 snails/0.1 m2 during the study period; however, no infections were identified in snails. Conclusions The endemic situation of schistosomiasis appears low in Tianmen City; however, the factors related to schistosomiasis transmission remain in the city. The integrated strategy with emphasis on the control of infectious sources should be still intensified to consolidate the schistosomiasis control achievements.

Chemically synthesized histone H2A Lys13 di-ubiquitination promotes binding of 53BP1 to nucleosomes.

This corrects the article DOI: 10.1038/cr.2017.157.

Total Chemical Synthesis of Modified Histones.

In the post-genome era, epigenetics has received increasing attentions in recent years. The post-translational modifications (PTMs) of four core histones play central roles in epigenetic regulation of eukaryotic genome by either directly altering the biophysical properties of nucleosomes or by recruiting other effector proteins. In order to study the biological functions and structural mechanisms of these histone PTMs, an obligatory step is to prepare a sufficient amount of homogeneously modified histones. This task cannot be fully accomplished either by recombinant technology or enzymatic modification. In this context, synthetic chemists have developed novel protein synthetic tools and state-of-the-art chemical ligation strategies for the preparation of homologous modified histones. In this review, we summarize the recent advances in the preparation of modified histones, focusing on the total chemical synthesis strategies. The importance and potential of synthetic chemistry for the study of histone code will be also discussed.

The convergent chemical synthesis of histone H3 protein for site-specific acetylation at Lys56 and ubiquitination at Lys122.

Deposition of (H3-H4)2 tetramers is believed to be the critical step in nucleosome assembly. Site-specific acetylation and ubiquitination of histone H3 have been speculated to synergistically facilitate the formation and deposition of (H3-H4)2 tetramers. Here we report our endeavors toward the first chemical synthesis of homogenous histone H3, which bears Lys56 acetylation and Lys122 ubiquitination, for in vitro biochemical and biophysical studies.

Causes of death after hip fracture in senile patients / 中华创伤杂志(英文版)

Hip trauma has been a leading cause of death in senile patients for more than a centenary. Although the mortality decreased due to the advanced technique in medication, surgery and nursing, the increasing mortality should not be neglected in elders after orthopedic operation nowadays. Many factors are considered to influence the causes of death after trauma, such as age, gender, personal customs, comorbidities, types of fracture, timing of surgery, procedure, anesthesia, complications, medical treatment, activity of daily living, or even marriage status. This article reviews these causes from the aspects of patient's own factors, iatrogenic factors, medical treatment and other factors and provides some clues for further clinical application according to the recent foreign and domestic researches. According to the present research, it is essential for surgeons to perform a comprehensive estimation for patients suffering from hip trauma.