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Civil war
This edition of the Civil War replaces the earlier Loeb Classical Library edition by A.G. Peskett (1914) with new text, translation, introduction, and bibliography.
Book
BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network
Inhibition of the tumour suppressive function of p53 (encoded by
TP53
) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)—the most common and deadly adult brain malignancy
1
,
2
. Thus, how p53-mediated tumour suppression is countered in
TP53
wild-type (
TP53
WT
) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in
TP53
WT
GBM. In line with these findings,
BRD8
is highly expressed with
H2AZ
in proliferating single cells of patient-derived GBM, and is inversely correlated with
CDKN1A
, a canonical p53 target that encodes p21 (refs.
3
,
4
). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with
TP53
WT
GBM.
BRD8 is identified as a specific epigenetic vulnerability for glioblastomas that harbour wild-type p53.
Journal Article
Neuronal enhancers are hotspots for DNA single-strand break repair
Defects in DNA repair frequently lead to neurodevelopmental and neurodegenerative diseases, underscoring the particular importance of DNA repair in long-lived post-mitotic neurons
1
,
2
. The cellular genome is subjected to a constant barrage of endogenous DNA damage, but surprisingly little is known about the identity of the lesion(s) that accumulate in neurons and whether they accrue throughout the genome or at specific loci. Here we show that post-mitotic neurons accumulate unexpectedly high levels of DNA single-strand breaks (SSBs) at specific sites within the genome. Genome-wide mapping reveals that SSBs are located within enhancers at or near CpG dinucleotides and sites of DNA demethylation. These SSBs are repaired by PARP1 and XRCC1-dependent mechanisms. Notably, deficiencies in XRCC1-dependent short-patch repair increase DNA repair synthesis at neuronal enhancers, whereas defects in long-patch repair reduce synthesis. The high levels of SSB repair in neuronal enhancers are therefore likely to be sustained by both short-patch and long-patch processes. These data provide the first evidence of site- and cell-type-specific SSB repair, revealing unexpected levels of localized and continuous DNA breakage in neurons. In addition, they suggest an explanation for the neurodegenerative phenotypes that occur in patients with defective SSB repair.
DNA single-strand breaks in neurons accumulate at high levelsin functional enhancers.
Journal Article
Crossing the Rubicon : Caesar's decision and the fate of Rome
A dramatic account of the fateful year leading to the ultimate crisis of the Roman Republic and the rise of Caesar's autocracy. When the Senate ordered Julius Caesar, conqueror of Gaul, to disband his troops, he instead marched his soldiers across the Rubicon River, in violation of Roman law. The Senate turned to its proconsul, Pompey the Great, for help. But Pompey's response was unexpected: he commanded magistrates and senators to abandon Rome-a city that, until then, had always been defended. The consequences were the ultimate crisis of the Roman Republic and the rise of Caesar's autocracy. In this new history, Luca Fezzi argues that Pompey's actions sealed the Republic's fate. Drawing on a wide range of primary sources, including Cicero's extensive letters, Fezzi shows how Pompey's decision shocked the Roman people, severely weakened the city, and set in motion a chain of events that allowed Caesar to take power. Seamlessly translated by Richard Dixon, this book casts fresh light on the dramatic events of this crucial moment in ancient Roman history.
Book
Cloning of the wheat Yr15 resistance gene sheds light on the plant tandem kinase-pseudokinase family
Yellow rust, caused by
Puccinia striiformis
f. sp.
tritici
(
Pst
), is a devastating fungal disease threatening much of global wheat production. Race-specific resistance (
R
)-genes are used to control rust diseases, but the rapid emergence of virulent
Pst
races has prompted the search for a more durable resistance. Here, we report the cloning of
Yr15
, a broad-spectrum
R
-gene derived from wild emmer wheat, which encodes a putative kinase-pseudokinase protein, designated as wheat tandem kinase 1, comprising a unique
R
-gene structure in wheat. The existence of a similar gene architecture in 92 putative proteins across the plant kingdom, including the barley RPG1 and a candidate for
Ug8
, suggests that they are members of a distinct family of plant proteins, termed here tandem kinase-pseudokinases (TKPs). The presence of kinase-pseudokinase structure in both plant TKPs and the animal Janus kinases sheds light on the molecular evolution of immune responses across these two kingdoms.
Yellow rust fungus severely limits global wheat production and breeding of durable resistance is challenging. Here Klymiuk et al. isolate the broad-spectrum
Yr15
resistance gene from wild emmer wheat and show that it is a member of a distinct tandem kinase-pseudokinase family of plant proteins.
Journal Article
Genetic basis and adaptation trajectory of soybean from its temperate origin to tropics
Soybean (
Glycine max
) serves as a major source of protein and edible oils worldwide. The genetic and genomic bases of the adaptation of soybean to tropical regions remain largely unclear. Here, we identify the novel locus
Time of Flowering 16
(
Tof16
), which confers delay flowering and improve yield at low latitudes and determines that it harbors the soybean homolog of
LATE ELONGATED HYPOCOTYL
(
LHY
).
Tof16
and the previously identified
J
locus genetically additively but independently control yield under short-day conditions. More than 80% accessions in low latitude harbor the mutations of
tof16
and
j
, which suggests that loss of functions of
Tof16
and
J
are the major genetic basis of soybean adaptation into tropics. We suggest that maturity and yield traits can be quantitatively improved by modulating the genetic complexity of various alleles of the
LHY
homologs,
J
and
E1
. Our findings uncover the adaptation trajectory of soybean from its temperate origin to the tropics.
How soybean, a temperate origin crop, adapted to a tropical environment remains unclear. Here, the authors report
Tof16
, an ortholog of
LHY
, and the previously identified
J
locus, control soybean yield under short-day condition and loss of function of these two genes contributes to the adaptation to tropics.
Journal Article
Super-enhancer hypermutation alters oncogene expression in B cell lymphoma
Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets
1
–
5
. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the
BCL6
,
BCL2
and
CXCR4
proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting
BCL6
) and the steroid receptor NR3C1 (targeting
BCL2
and
CXCR4
). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.
Active super-enhancers are highly and specifically hypermutated in 92% of diffuse large B cell lymphoma samples and display signatures of activation-induced cytidine deaminase activity, leading to the dysregulation of genes encoding B cell developmental regulators and oncogenes.
Journal Article