Sarcoma_CellminerCDB: A tool to interrogate the genomic and functional characteristics of a comprehensive collection of sarcoma cell lines.

Sarcomas are a diverse group of rare malignancies composed of multiple different clinical and molecular subtypes. Due to their rarity and heterogeneity, basic, translational, and clinical research in sarcoma has trailed behind that of other cancers. Outcomes for patients remain generally poor due to an incomplete understanding of disease biology and a lack of novel therapies. To address some of the limitations impeding preclinical sarcoma research, we have developed Sarcoma_CellMinerCDB, a publicly available interactive tool that merges publicly available sarcoma cell line data and newly generated omics data to create a comprehensive database of genomic, transcriptomic, methylomic, proteomic, metabolic, and pharmacologic data on 133 annotated sarcoma cell lines. The reproducibility, functionality, biological relevance, and therapeutic applications of Sarcoma_CellMinerCDB described herein are powerful tools to address and generate biological questions and test hypotheses for translational research. Sarcoma_CellMinerCDB (https://discover.nci.nih.gov/SarcomaCellMinerCDB) aims to contribute to advancing the preclinical study of sarcoma.

The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes.

TOP3B is stabilized by TDRD3. Hypothesizing that TDRD3 recruits a deubiquitinase, we find that TOP3B interacts with USP9X via TDRD3. Inactivation of USP9X destabilizes TOP3B, and depletion of both TDRD3 and USP9X does not promote further TOP3B ubiquitylation. Additionally, we observe that MIB1 mediates the ubiquitylation and proteasomal degradation of TOP3B by directly interacting with TOP3B independently of TDRD3. Combined depletion of USP9X, TDRD3 and MIB1 causes no additional increase in TOP3B levels compared to MIB1 knockdown alone indicating that the TDRD3-USP9X complex works downstream of MIB1. To comprehend why cells degrade TOP3B in the absence of TDRD3, we measured TOP3Bccs. Lack of TDRD3 increases TOP3Bccs in DNA and RNA, and induced R-loops, γH2AX and growth defect. Biochemical experiments confirm that TDRD3 increases the turnover of TOP3B. Our work provides molecular insights into the mechanisms by which TDRD3 protect cells from deleterious TOP3Bccs which are otherwise removed by TRIM41.

Multifaceted activities of DNA polymerase η: beyond translesion DNA synthesis.

DNA polymerases are evolved to extend the 3'-OH of a growing primer annealed to a template DNA substrate. Since replicative DNA polymerases have a limited role while replicating structurally distorted template, translesion DNA polymerases mostly from Y-family come to the rescue of stalled replication fork and maintain genome stability. DNA polymerase eta is one such specialized enzyme whose function is directly associated with casual development of certain skin cancers and chemo-resistance. More than 20 years of extensive studies are available to support TLS activities of Polη in bypassing various DNA lesions, in addition, limited but crucial growing evidence also exist to suggest Polη possessing TLS-independent cellular functions. In this review, we have mostly focused on non-TLS activities of Polη from different organisms including our recent findings from pathogenic yeast Candida albicans.

Cysteine mediated disulfide bond formation in RAGE V domain facilitates its functionally relevant dimerization.

Receptor for Advanced Glycation End product (RAGE) is a multiligand receptor implicated in diverse pathological conditions such as diabetes, atherosclerosis, cancer and neural diseases. Extracellular, RAGE consists of V, C1 and C2 domains. Here, we show RAGE exists as a monomer in equilibrium with a fraction of a covalently linked dimer of monomers via its V domain through cysteine. In order to understand the functional implication of this dimer, we examined the binding capacity and functional potential of RAGE dimer via advanced glycation end products (AGEs) which shows enhanced binding capacity towards V domain, ERK phosphorylation, cytokine release and actin polymerization ability of the dimeric form for AGEs compared with the reduced monomeric form. Our data, suggests that the dimeric state of RAGE controls its function and ligand mediated signaling which may play important role in RAGE mediated various diseases.