Revealing the Determinants of Widespread Alternative Splicing Perturbation in Cancer

It is increasingly appreciated that alternative splicing
plays a key role in generating functional specificity
and diversity in cancer. However, the mechanisms
by which cancer mutations perturb splicing remain
unknown. Here, we developed a network-based strategy,
DrAS-Net, to investigate more than 2.5 million
variants across cancer types and link somatic mutations
with cancer-specific splicing events. We identi-
fied more than 40,000 driver variant candidates and
their 80,000 putative splicing targets deregulated in
33 cancer types and inferred their functional impact.
Strikingly, tumors with splicing perturbations show
reduced expression of immune system-related
genes and increased expression of cell proliferation
markers. Tumors harboring different mutations in
the same gene often exhibit distinct splicing perturbations.
Further stratification of 10,000 patients based
on their mutation-splicing relationships identifies
subtypes with distinct clinical features, including survival
rates. Our work reveals how single-nucleotide
changes can alter the repertoires of splicing isoforms,
providing insights into oncogenic mechanisms for
precision medicine.

The paper by Li et al can be found here.

Constraints and consequences of the emergence of amino acid repeats in eukaryotic proteins

Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases.
Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential
and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of
proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution,
homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated
detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein
divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational-modification
sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct
modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype–
phenotype landscape of a population, thereby contributing to adaptation and fitness.

The paper by Chavali et al can be found here.