Biology subjects

Marcelain, K.

Publications and source records attributed to Marcelain, K..

3 recordsLinked to original sources

bioRxiv2025

ADAR1 regulates alternative splicing through an RNA editing-independent mechanism.

Adenosine-to-inosine (A-to-I) RNA editing and alternative splicing occur co-transcriptionally and can regulate and influence each other. The RNA editing enzymes ADAR1 and ADAR2 catalyze A-to-I RNA editing, where it has been shown that expression changes in both RNA editing enzymes exert alternative splicing. ADAR1 manipulation has a significant impact on alternative splicing. While many of those changes are related to changes in their A-to-I RNA editing activity, we speculate that ADAR1 may also influence splicing in an editing-independent manner. In this work, the protein-protein interactome of ADAR1 revealed that ADAR1 interacts with spliceosome co-factors and auxiliary splicing regulators. We confirmed that ADAR1 does not only influence splicing through editing but also throughout editing-independent functions with even greater penetrance. We show that ADAR1 modulates the splicing of transcripts encoding splicing factors, with many of these splice sites overlapping with known splicing changes induced by the splicing factor ACIN1, suggesting indirect effects upon ADAR1 expression. In summary, we show that ADAR1 can regulate splicing in an editing-independent manner, which likely occurs by widespread alteration of the splicing factor isoform landscape.

molecular biology↗

bioRxiv2024

Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease

Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and here we investigated the association between inbreeding, GBC, gallstone disease (GSD) and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions between FROH and sex, age, and genetic risk of GSD on GBC risk. Specifically, the increase in GBC risk per 1% FROH was 19% in men (P-value = 0.002), 30% in those under 60 years of age (P-value = 0.001), and 12% in those with a genetic risk of GSD above the median (P-value = 0.01). The present study highlights the complex interplay between inbreeding, genetic ancestry and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscore the importance of considering the population-specific genetic architecture, along with sex- and age specific-effects, when investigating the genetic basis of complex traits in Latin Americans.

genetics↗

bioRxiv2022

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.

cancer biology↗