Structural basis for retroviral integration into nucleosomes

Maskell, Daniel P.; Renault, Ludovic; Serrao, Erik; Lesbats, Paul; Matadeen, Rishi; Hare, S.; Lindemann, Dirk; Engelman, Alan; Costa, Alessandro; Cherepanov, Peter

doi:10.1038/nature14495

Cited by 137 publications

(299 citation statements)

References 49 publications

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“…Unfortunately, there are no structures of pioneer factors bound to a nucleosome, and the existing structures of nucleosome corebinding proteins bound to a NCP are nonspecific complexes that make little contact with NCP DNA (20,22,30). The recent structure of the prototype foamy virus integrase bound to NCP shows that this enzyme makes substantial contact with SHL ±3.5, but the low resolution does not permit a deeper analysis (31). The integrase binds preferentially to SHL +3.5, and though the dyad position (origin) of the D02 DNA fragment most thoroughly studied is not known to base-pair accuracy, AG′GTAG,TT [prime sign (′) and comma (,) denote integration cleavage sites] is the sequence mapped at this location.…”

Section: Discussionmentioning

confidence: 99%

X-ray structure of the MMTV-A nucleosome core

Frouws

Duda

Richmond

2016

Proc. Natl. Acad. Sci. U.S.A.

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The conformation of DNA bound in nucleosomes depends on the DNA sequence. Questions such as how nucleosomes are positioned and how they potentially bind sequence-dependent nuclear factors require near-atomic resolution structures of the nucleosome core containing different DNA sequences; despite this, only the DNA for two similar α-satellite sequences and a sequence (601) selected in vitro have been visualized bound in the nucleosome core. Here we report the 2.6-Å resolution X-ray structure of a nucleosome core particle containing the DNA sequence of nucleosome A of the 3′-LTR of the mouse mammary tumor virus (147 bp MMTV-A). To our knowledge, this is the first nucleosome core particle structure containing a promoter sequence and crystallized from Mg 2+ ions. It reveals sequence-dependent DNA conformations not seen previously, including kinking into the DNA major groove.chromatin | nucleosome | DNA | X-ray structure | MMTV D NA in eukaryotic cells is wrapped repeatedly in nucleosomes to form chromatin, the substrate engaged by the nuclear machinery to carry out repair, replication, recombination, and transcription of genomes. Nucleosome mapping in situ combined with biochemical studies has revealed that nucleosome positions determine access to DNA regulatory sequences essential to these processes (1, 2). Nucleosome position is determined chiefly by DNA sequence and ATP-dependent chromatin remodeling factors (3-5). The nucleosome includes a linker DNA of variable length and a nucleosome core containing a histone octamer and 147 bp of DNA (6). Many high-resolution structures of nucleosome cores with differing DNA sequences are required to see how the details of DNA conformation could affect nucleosome positioning and dynamics, as well as nuclear factor binding. The DNA studied would most interestingly represent natural sequences of transcription promoters and enhancer elements.Our knowledge of sequence-dependent structure of DNA bound in the nucleosome core relative to the amount of DNA bound in genomes is extremely limited. A resolution of at least 2.6 Å is necessary to evaluate differences in DNA conformations and assess solvent interactions adequately. To date, this highly reliable "library" of DNA structural information pertinent to the nucleosome core consists primarily of two similar sequences of half α-satellite repeats and half the artificially "evolved" sequence 601 (7-10). Further investigations have been limited to substitution of short sequence elements in one of the α-satellite sequences (11, 12). These high-resolution structures have hinged on using palindromic sequences to avoid twofold averaging imposed by crystal packing. The lack of twofold symmetry in the full 601 sequence, for example, resulted in superposition of the electron density of the two different half-sequences (9).We describe here the X-ray structure of a nucleosome core particle (NCP) containing a DNA sequence from mouse mammary tumor virus (MMTV) determined at 2.6 Å resolution. To our knowledge, this is the first NCP structure conta...

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Section: Discussionmentioning

confidence: 99%

X-ray structure of the MMTV-A nucleosome core

Frouws

Duda

Richmond

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These properties depend at least in part on the interaction between integrase and bromodomain proteins BRD2-4 (19)(20)(21). In contrast, prototype foamy virus (PFV), a member of the generally benign spumavirus retroviral genus, appears to be averse to generich regions and disfavors integration into genes (22). Encouraged by earlier observations that PFV GAG can bind chromatin (23,24), we determined a crystal structure of its chromatin-binding sequence (CBS) bound to a mononucleosome.…”

mentioning

confidence: 99%

Structural basis for spumavirus GAG tethering to chromatin

Lesbats

Serrao

Maskell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The interactions between a retrovirus and host cell chromatin that underlie integration and provirus expression are poorly understood. The prototype foamy virus (PFV) structural protein GAG associates with chromosomes via a chromatin-binding sequence (CBS) located within its C-terminal region. Here, we show that the PFV CBS is essential and sufficient for a direct interaction with nucleosomes and present a crystal structure of the CBS bound to a mononucleosome. The CBS interacts with the histone octamer, engaging the H2A-H2B acidic patch in a manner similar to other acidic patch-binding proteins such as herpesvirus latency-associated nuclear antigen (LANA). Substitutions of the invariant arginine anchor residue in GAG result in global redistribution of PFV and macaque simian foamy virus (SFV mac ) integration sites toward centromeres, dampening the resulting proviral expression without affecting the overall efficiency of integration. Our findings underscore the importance of retroviral structural proteins for integration site selection and the avoidance of genomic junkyards.retrovirus | integration | nucleosome | chromatin-binding

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“…Both nucleosomal and linker DNA can be strongly bound by modifying enzymes and complexes, which must be first targeted to DNA by specific transcription factors in a selective fashion. In the future, it will be interesting to see how widespread the role of DNA "malleability" is, a characteristic suggested to be crucial by the investigation on intasome complex (Maskell et al, 2015) and, very recently, by the structural studies on RNA polymerase stalled on the nucleosome (Gaykalova et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The malleability of DNA can underline selective nucleosome recognition, a concept that is beautifully demonstrated in recently reported work on the mechanism of retroviral DNA integration into the genome (Maskell et al, 2015). It is known that retroviruses use their integral transposases to severely bend and distort target DNA and disrupt backbone phosphodiester bonds for integration (Kvaratskhelia et al, 2014).…”

Section: Dna Deformation In Nucleosome Recognitionmentioning

confidence: 99%

Touch, act and go: landing and operating on nucleosomes

et al. 2016

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Chromatin-associated enzymes are responsible for the installation, removal and reading of precise post-translation modifications on DNA and histone proteins. They are specifically recruited to the target gene by associated factors, and as a result of their activity, they contribute in modulating cell identity and differentiation. Structural and biophysical approaches are broadening our knowledge on these processes, demonstrating that DNA, histone tails and histone surfaces can each function as distinct yet functionally interconnected anchoring points promoting nucleosome binding and modification. The mechanisms underlying nucleosome recognition have been described for many histone modifiers and related readers. Here, we review the recent literature on the structural organization of these nucleosome-associated proteins, the binding properties that drive nucleosome modification and the methodological advances in their analysis. The overarching conclusion is that besides acting on the same substrate (the nucleosome), each system functions through characteristic modes of action, which bring about specific biological functions in gene expression regulation.

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Structural basis for retroviral integration into nucleosomes

Cited by 137 publications

References 49 publications

X-ray structure of the MMTV-A nucleosome core

X-ray structure of the MMTV-A nucleosome core

Structural basis for spumavirus GAG tethering to chromatin

Touch, act and go: landing and operating on nucleosomes

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