This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron

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Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineage, BA.1 (ref1, 2), another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Heterogeneous nuclear ribonucleoprotein D, also known as AUF1, has two DNA/RNA-binding domains, each of which can specifically bind to single-stranded d(TTAGGG) n , the human telomeric repeat. Here, the structure of the C-terminal-binding domain (BD2) complexed with single-stranded d(TTAGGG) determined by NMR is presented. The structure has revealed that each residue of the d(TAG) segment is recognized by BD2 in a base-specific manner. The interactions deduced from the structure have been confirmed by gel retardation experiments with mutant BD2 and DNA. It is known that single-stranded DNA with the telomeric repeat tends to form a quadruplex and that the quadruplex has an inhibitory effect on telomere elongation by telomerase. This time it is revealed that BD2 unfolds the quadruplex of such DNA upon binding. Moreover, the effect of BD2 on the elongation by telomerase was examined in vitro. These results suggest the possible involvement of heterogeneous nuclear ribonucleoprotein D in maintenance of the telomere 3-overhang either through protection of a single-stranded DNA or destabilization of the potentially deleterious quadruplex structure for the elongation by telomerase. Heterogeneous nuclear ribonucleoprotein (hnRNP)1 D, also known as AUF1, was isolated from a HeLa cell nuclear extract as a protein that binds specifically to single-stranded d(T-TAGGG) n , the human telomeric DNA repeat (1). It also binds to r(UUAGGG) n (1) and the AU-rich element of the 3Ј-untranslated region of mRNA (2). It was shown biochemically that hnRNP D binding to the Gua-rich telomeric strand d(T-TAGGG) n destabilizes intrastrand Gua:Gua pairing and that hnRNP D interacts specifically with telomerase in human cell extracts (3). Thus, the involvement of hnRNP D in the maintenance of telomere DNA has been implied.hnRNP D consists of 306 amino acid residues and comprises two ribonucleoprotein (RNP)-type DNA/RNA-binding domains (BDs), BD1 (70 -173) and BD2 (174 -256), and a region rich in glycine and arginine residues (257-306) (4). The RNP-type BD is one of the most common eukaryotic protein sequence motifs for DNA/RNA binding (5), being found in hundreds of proteins (6 -9). A single BD of hnRNP D, either BD1 or BD2, is able to bind to DNA and RNA in a sequence-specific manner (4, 10, 11). The binding affinity of either BD1 or BD2 is comparable with that of the protein having both BD1 and BD2 (4). These results suggest that the basis of the interactions of hnRNP D with DNA and RNA can be addressed by examination with a single BD. We have already reported the structures of BD1 (10) and BD2 (11). We also qualitatively identified the surfaces of BD1 (10) and BD2 (11) interactive with DNA and RNA on chemical shift perturbation analysis, although it should be kept in mind that the perturbation is caused not only through the direct interaction but also thorough the indirect effect of the interaction. Essentially the same surfaces of the BDs are used for the interactions with DNA and RNA.Here, we present the structure of BD2 complexed with d(...

Recent studies have revealed the unique virological characteristics of Omicron, the newest SARS-CoV-2 variant of concern, such as pronounced resistance to vaccine-induced neutralizing antibodies, less efficient cleavage of the spike protein, and poor fusogenicity. However, it remains unclear which mutation(s) in the spike protein determine the virological characteristics of Omicron. Here, we show that the representative characteristics of the Omicron spike are determined by its receptor-binding domain. Interestingly, the molecular phylogenetic analysis revealed that the acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidate that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue in another protomer in the spike trimer, which confers the attenuated spike cleavage efficiency and fusogenicity of Omicron. Our data shed light on the evolutionary events underlying Omicron emergence at the molecular level.