Biology subjects

Nikolaev, S. I.

Publications and source records attributed to Nikolaev, S. I..

3 recordsLinked to original sources

bioRxiv2024

Single-cell Transcriptome Profiling of Post-treatment and Treatment-naive Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Analyzing changes within tumor cells and tumor microenvironment (TME) after treatment and in metastases is essential to understanding how resistance develops. In this study, we analyzed scRNA-seq data from 56 CRCs including treatment-naive tumors and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). In our cohort, primary left-sided CRCs were associated with metastatic potential mesenchymal phenotype and with depleted B cells. In the post-treatment CRC, there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. In progressors there was an enrichment of pericyte-like fibroblasts, which appeared to be associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated fractions of exhausted CD8+ T memory cells suggesting a pro-inflammatory TME. In tumor cells of progressors group, we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related immune-checkpoint CD24. In summary, scRNA-seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features potentially underlying response to chemotherapy or disease progression in CRC.

cancer biology↗

bioRxiv2022

Analysis of Skin Cancers from Xeroderma Pigmentosum Patients Reveals Heterogeneous UV-Induced Mutational Profiles Shaped by DNA Repair

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis (TLS) DNA polymerase {eta} (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyzed 38 skin cancer genomes from five XP groups. We found that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH-KO cell line revealed the role of polymerase {eta} in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3 nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

cancer biology↗

bioRxiv2017

Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Spontaneously occurring mutations are of great relevance in diverse fields including biochemistry, oncology, evolutionary biology, and human genetics. Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity as well as many forms of DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutations remain completely unknown. Here, based on the mutational asymmetry with respect to the direction of replication and transcription, we suggest that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Asymmetry with respect to transcription is believed to be mediated by the action of transcription-coupled DNA repair (TC-NER). TC-NER selectively repairs DNA lesions on the transcribed strand; as a result, lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between transcriptional asymmetry and asymmetry with respect to replication fork direction. This parallels the observation that damage-induced mutations in human cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are asymmetrically resolved during replication. Re-analysis of XR-seq data, Damage-seq data and cancers with defective NER corroborate the preferential error-prone bypass of DNA lesions on the lagging strand. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of UV-irradiation, in line with the key role of replication in conversion of DNA damage to mutations. We conservatively estimate that at least 10% of human germline mutations arise due to DNA damage rather than replication infidelity. The number of these damage-induced mutations is expected to scale with the number of replications and, consequently, paternal age.

biochemistry↗