Biology subjects

Rusanov, T.

Publications and source records attributed to Rusanov, T..

3 recordsLinked to original sources

bioRxiv2025

Integrative analysis of spatiotemporal transcriptomics delineates dynamic cell states in squamous tumorigenesis

Squamous cell cancers are responsible for 1 in 5 cancer deaths and survival improvements lag behind those seen in adenocarcinomas. This disparity is in large part due to the limited impact of immunotherapy due to therapeutic resistance, where less than ten percent of patients respond in early stage squamous cell carcinomas of the Head and Neck. Mechanisms that govern intrinsic resistance remain poorly understood and likely arise during the premalignant or dysplastic state. Here, we generated a dataset of murine and human oral squamous epithelia spanning the earliest premalignant stages through invasive carcinoma. Integrative analysis of single-cell and spatial transcriptomics data across the dysplasia to carcinoma continuum reveals early and sustained shifts in epithelial transcriptomes. Spatially informed cell-cell interaction analysis reveals dysplasia-specific upregulation of wound healing and immune remodeling programs in severe dysplasia and invasive carcinoma in a human sample of oral dysplasia. The presence of these transcriptomic programs within early dysplasia may account for the aggressive clinical presentations of squamous cancers including intrinsic therapeutic resistance.

cancer biology↗

bioRxiv2022

A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichiothiodystrophy

The pre-mRNA life cycle requires intron processing; yet, how intron processing defects influence splicing and gene expression is unclear. Here, we find TTDN1, which is frequently mutated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to the spliceosome. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, while its N-terminal intrinsically disordered region (IDR) binds the intron binding complex (IBC). The IDR forms condensates in vitro and is needed for IBC interaction. TTDN1 loss causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. Ttdn1{Delta}/{Delta} mice recapitulate intron processing defects and neurodevelopmental phenotypes seen in NP-TTD. A DBR1-IDR fusion recruits DBR1 to the IBC and circumvents the requirement for TTDN1, indicating this tethering role as its major molecular function. Collectively, our findings unveil key functional connections between lariat processing, splicing outcomes, and NP-TTD molecular pathology.

biochemistry↗

bioRxiv2021

The ASCC2 CUE domain contacts adjacent ubiquitins to recognize K63-linked polyubiquitin

Alkylation of DNA and RNA is a potentially toxic lesion that can result in mutations and cell death. In response to alkylation damage, K63-linked polyubiquitin chains are assembled that localize the ALKBH3-ASCC repair complex to damage sites in the nucleus. The protein ASCC2, a subunit of the ASCC complex, selectively binds K63-linked polyubiquitin chains using its CUE domain, a type of ubiquitin-binding domain that typically binds monoubiquitin and does not discriminate among different polyubiquitin linkage types. We report here that the ASCC2 CUE domain selectively binds K63-linked diubiquitin by contacting both the distal and proximal ubiquitin. Whereas the ASCC2 CUE domain binds the distal ubiquitin in a manner similar to that reported for other CUE domains bound to a single ubiquitin, the contacts with the proximal ubiquitin are unique to ASCC2. The N-terminal portion of the ASCC2 1 helix, including residues E467 and S470, contributes to the binding interaction with the proximal ubiquitin of K63-linked diubiquitin. Mutation of residues within the N-terminal portion of the ASCC2 1 helix decreases ASCC2 recruitment in response to DNA alkylation, supporting the functional significance of these interactions during the alkylation damage response.

biophysics↗