The genetic heterogeneity hampers the identification of biomarkers for Stomach adenocarcinoma (STAD). Here, we proposed a new pipeline to screen the cross-cohort reliable prognostic RNA signatures, and to develop practically applicable models predicting the gastric cancers with shortest and longest overall survival. A strategy of bi-end stratification combined with supervised comparison and LASSO regression was proposed, which could largely improve the statistical power in identification of prognostic gene signatures. By the strategy, we identified 12 signature genes whose expression was associated with the poorest prognosis, and other 12 genes associated with the best prognosis of STAD. Stably expressed genes (SEGs) among different cell types of normal and diseased stomachs were identified using single-cell RNA-seq data, expression levels of the signature genes were normalized with these SEGs, and multi-gene Cox models were built with the normalized expression of the signature genes with the training cohort. The models could well predict the STAD cases of poorest and best prognosis. Combination of stage information further improved the prediction performance, with the accuracy reaching 0.69–0.84 for poorest prognosis and 0.75–0.81 for best prognosis prediction in independent STAD cohorts. The study identified cross-cohort stable STAD prognosis-associated genes, and developed two practically applicable multi-gene models identifying STAD cases of poorest and best prognosis effectively.
The ATM (Ataxia telangiectasia mutated) kinase and its complex with TIP60 could rapidly respond to DNA double-strand breaks. But the molecular mechanism remains elusive. New research identifies FAM135B as a novel regulator of TIP60-ATM axis. FAM135B interacts with and maintains the TIP60-ATM reservoir in resting condition, whereas it dissociates from the complex and degrades, allowing cells to respond to DNA damage. This work reveals a direct link between the steady-state organization of ATM and the kinetics of its activation after DNA damage.
G-quadruplex (G4) is a non-canonical DNA second structure formed on specific G-rich sequences which are enriched in transcriptional regulatory regions and telomeres. This structure is involved in multiple cellular processes including transcription regulation and genome integrity. On the other hand, G-rich regions are hotspots of oxidative damage, since G has the lowest redox potential among the four nucleobases, and the 5’G of a G stretch has an even lower ionization potential. Evidence emerged recently that the most common oxidative damage, 8-oxo-7,8-dihydroguanine (OG), plays an epigenetic-like role to regulate transcription. Therefore, G4 and OG may co-localize at G-rich regions and interact with each other to regulate transcription. In this review, we summarize recent advantages about genome-wide mapping of G4 and OG, and discuss their crosstalk at genomic level.
Single-stranded DNA (ssDNA) is a common intermediate produced during normal DNA transactions, including transcription, DNA replication, repair, and recombination. Replication protein A (RPA), an evolutionarily conserved ssDNA-binding protein complex, plays a critical role in these DNA transactions through its dynamic association with ssDNA or proteins. The binding of RPA on ssDNA protects ssDNA from unscheduled nuclease digestion, melts secondary DNA structures, suppresses mutations, and signals the checkpoint for DNA damage or replication stresses. In parallel, RPA serves as a platform for interacting with a number of different proteins to coordinate various DNA metabolic processes. However, our understanding of the regulation and function of RPA is far from complete. Here, we reviewed recent advances on the roles of RPA in regulating replication, repair, nucleosome assembly, rDNA transcription, chromatin epigenetic landscape, and chromosome segregation. In addition, we described the interplay between RPA and the ubiquitin E3 ligase RFWD3 that determines RPA turnover at replication forks or DNA lesion sites. These new findings advance our understanding of the versatile roles of RPA in preserving genome integrity and could provide opportunities to develop therapeutic strategies targeting cancer.
Microcephaly primary hereditary (MCPH) is a rare, neurological disorder characterized by a small brain size, due to a lower number of neural progenitor cells, and mental retardation (Naveed in Genetics Research 100:e7, 2018). Approximately 40% of all MCPH patients harbor mutations in abnormal spindle-like microcephaly-associated (ASPM) gene, which is also known as MCPH5 (Létard in Human Mutation 39(3):319–32, 2018). The ASPM protein is involved in centriole duplication, orientation of the spindle, and regulation of mitosis (Jiang in Nature Cell Biology 19(5):480–492, 2017; Gai in EMBO Reports 17(10):1396–1409, 2016). Although these functions of ASPM seem to be independent of DNA replication, impaired DNA replication has been associated with microcephaly (Tingler in Biology of the Cell 114(6):143–159; Kalogeropoulou in Stem Cell Reports 17(6):1395–1410; Xu in Genome Instability & Disease 1:235–264). In a recent PNAS paper by Wu et al., the authors suggested that patients with mutations in ASPM harbor a reduced number of neuroprogenitor cells due to defects in the DNA stress response.