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New work on DNA polymerase λ highlights its remarkable flexibility. This fits with the generally adaptable nature of the DNA-repair process in which this enzyme is involved—nonhomologous end-joining—which allows this mechanism to handle diverse types of broken DNA ends in order to restore the duplex structure, albeit with a loss of information at the join.
Nuclear actin polymerization helps facilitate chromosome compartment switches that can shift damaged DNA toward a nuclear environment that is favorable for DNA repair. Yet shifting multiple broken DNA strands together can also increase the likelihood of misjoining of the DNA ends and subsequent formation of translocations.
In this Perspective the authors discuss the major challenges when studying the role of enhancers in disease etiology, highlighting a path forward for future studies aiming to understand the molecular basis of enhanceropathies.
New research shows that the CoREST complex controls the acquisition of endocrine therapy resistance in estrogen receptor-positive breast cancers. Profiling data show that this resistance transition is accompanied by a functional retargeting of CoREST on chromatin in coordination with cJUN and SWI/SNF (cBAF).
Recent structures of the three-way complex formed by the scaffold protein SHOC2, the small G protein M-RAS and protein phosphatase 1 (PP1) provide a tantalizing insight into the activation of RAF, the oncogenic kinase and downstream effector of RAS that drives cell proliferation and survival.
The mechanisms by which translesion DNA polymerases mediate DNA repair are incompletely understood. A new study shows that Escherichia coli DNA polymerase IV is concentrated at the sites of arrested DNA synthesis by an interaction with SSB, the major single-stranded DNA-binding protein, specifically at stalled but not ongoing replication forks.
New cryo-EM structures of the FANCD2–FANCI complex provide insights into how phosphorylation of FANCI facilitates DNA clamping to prime the complex for monoubiquitination and recruitment of downstream factors in the Fanconi anemia pathway of DNA damage repair.
A study published in Nature Structural & Molecular Biology now unveils, at the atomic level, the initial mechanisms of prion toxicity, providing insights into the pathogenic mechanisms of a protein neurodegenerative disease caused by protein misfolding.
CST is both an ssDNA-binding complex and a DNA Pol-α/primase cofactor that coordinates the switch from G-strand elongation to C-strand fill-in during telomere maintenance. Four papers in Nature Structural & Molecular Biology and Nature provide transformative insights into CST activity, providing a platform to understand lagging-strand synthesis genome wide.
Amplification of oncogene expression through extrachromosomal DNA is a common feature of many cancers and is associated with poor outcomes. Hung et al. review how regulation of extrachromosomal DNA gene expression is linked to alterations in chromatin structure and changes in contacts with DNA regulatory elements.
Structural maintenance of chromosomes (SMC) complexes such as condensin regulate chromosome organization by extruding loops. A new study uses single-molecule imaging of condensin on supercoiled DNA to understand how condensins navigate the under- and overwound DNA states common throughout the genome.
Two new papers describe the successful purification of the partially intact human native red blood cell band 3 multiprotein membrane complexes, providing information that the authors then use to capture the structures and interactions of multiple erythrocyte proteins using high-resolution cryo-EM.
MFSD2A mediates uptake of the essential fatty acid DHA across the blood–brain barrier. Separately, via interactions with syncytin-2, MFSD2A contributes to the formation of the mother–fetus placental boundary. Cryo-EM analysis of a human MFSD2A–syncytin-2 complex provides new insights into how MFSD2A performs these dual roles.
The central apparatus regulates the beating of motile cilia. High-resolution structures of the almost complete central apparatus are now reported in two separate studies, shedding light on the mechanism of ciliary beating and marking a new era in our molecular understanding of cilia architecture and function.
The CRISPR–Cas enzyme Cas9 faces the challenge of identifying a specific nucleotide sequence within double-stranded DNA. New cryo-EM and biochemical studies show that in the earliest steps of binding, Cas9 bends the DNA and promotes unwinding of two base pairs, enabling it to efficiently scan the sequence of this critical region.
