一周快讯：本周表观文献精选（2018.2.27）

Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress

Morgane Macheret & Thanos D. Halazonetis

原文链接：

https://www.nature.com/articles/nature25507

原文摘要：Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer However, elucidating how oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 and MYC. Remarkably, both oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.

Evolutionary analysis indicates that DNA alkylation damage is a byproduct of cytosine DNA methyltransferase activity

Silvana Rošić  Rachel Amouroux , Cristina E. Requena, Ana Gomes, Max Emperle, Toni Beltran ，Jayant K. Rane, Sarah Linnett,Murray E. Selkirk ，Philipp H. Schiffer, Allison J. Bancroft, Richard K. Grencis, Albert Jeltsch  Petra Hajkova  & Peter Sarkies

原文链接：

https://www.nature.com/articles/s41588-018-0061-8

原文摘要：

Methylation at the 5 position of cytosine in DNA (5meC) is a key epigenetic mark in eukaryotes. Once introduced, 5meC can be maintained through DNA replication by the activity of ‘maintenance’ DNA methyltransferases (DNMTs). Despite their ancient origin, DNA methylation pathways differ widely across animals, such that 5meC is either confined to transcribed genes or lost altogether in several lineages. We used comparative epigenomics to investigate the evolution of DNA methylation. Although the model nematode Caenorhabditis elegans lacks DNA methylation, more basal nematodes retain cytosine DNA methylation, which is targeted to repeat loci. We found that DNA methylation coevolved with the DNA alkylation repair enzyme ALKB2 across eukaryotes. In addition, we found that DNMTs introduced the toxic lesion 3-methylcytosine into DNA both in vitro and in vivo. Alkylation damage is therefore intrinsically associated with DNMT activity, and this may promote the loss of DNA methylation in many species.

Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes

Longsen Han, Chao Ren, Ling Li, Xiaoyan Li, Juan Ge, Haichao Wang, Yi-Liang Miao ， Kelle H. Moley, Qiang Wang  & Wenjie Shu

原文链接：

https://www.nature.com/articles/s41588-018-0055-6

原文摘要：Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions. Furthermore, methylome-wide sequencing analysis detected global hypomethylation across the zygote genome in HFD-fed mice, with a specific enrichment in transposon elements and unique regions. Notably, overexpression of Stella in the oocytes of HFD-fed mice not only restored the epigenetic remodeling in zygotes but also partly ameliorated the maternal-obesity-associated developmental defects in early embryos and fetal growth. Thus, Stella insufficiency in oocytes may represent a critical mechanism that mediates the phenotypic effects of maternal obesity in embryos and offspring.

RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells

Mark A. Hawk, Cassandra L. Gorsuch, Patrick Fagan, Chan Lee, Sung Eun Kim, -Jens C. Hamann, Joshua A. Mason, Kelsey J. Weigel, Matyas Abel Tsegaye, Luqun Shen, Sydney Shuff, Junjun Zuo, Stephan Hu， Lei Jiang, Sarah Chapman, W. Matthew Leevy, Ralph J. DeBerardinis, Michael Overholtzer & Zachary T. Schafer

原文链接：

https://www.nature.com/articles/s41556-018-0034-2

原文摘要：For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH productionin the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.