Biology subjects

Valle, L.

Publications and source records attributed to Valle, L..

3 recordsLinked to original sources

bioRxiv2022

Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors.

Somatic POLE mutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541 POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as POLE ExoD driver, POLE ExoD driver plus POLE Variant, and POLE Variant TMB-H. Intriguingly, TMB was highest in tumors bearing POLE ExoD driver plus POLE Variant (p<0.001 in CRC and EC, p<0.05 in OC). Integrated analysis of AlphaFold2-modeled POLE models and quantitative estimate of stability indicated that multiple variants had significant impact on functionality. These data indicate that co-occurring POLE variants categorize a unique subset of POLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes. SignificanceSomatic POLE ExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations in POLE ExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.

cancer biology↗

bioRxiv2022

Extended family with germline pathogenic variant in polymerase delta provides strong evidence for recessive effect of proofreading inactivation

Mutational processes in germline and in somatic cells are vastly different, and it remains unclear how the same genetic background affects somatic and transmissible mutations. Here, we estimate the impact of an inherited pathogenic variant in the exonuclease domain of polymerase delta (Pol{delta}) on somatic and germline mutational processes and cancer development. In germline cells and in non-cancer somatic cells, the POLD1 L474P variant increases the mutation burden only slightly, contributing [~]11.8% and [~]14.7% of mutations respectively, although it strongly distorts the mutational spectra. By contrast, tumors developed by carriers of inherited pathogenic variants in POLD1 harbor a DNA rearrangement that results in a homozygous state of the pathogenic variant, leading to an extremely high mutation rate. Thus, mutations in both alleles of POLD1 gene are required for strong increase in mutation rate suggesting recessiveness of Pold{delta} proofreading. These results show a similar role of Pol{delta} in germline and somatic replication, and, together with previous findings, illustrate the important differences between Pol{delta} and Pol{varepsilon} in the disruption of their replication fidelity.

genetics↗

bioRxiv2021

Characterization of BLUF-photoreceptors present in Acinetobacter nosocomialis.

Acinetobacter nosocomialis is a Gram-negative opportunistic pathogen, whose ability to cause disease in humans is well recognized. Blue light has been shown to modulate important physiological traits related to persistence and virulence in this microorganism. In this work, we characterized the three Blue Light sensing Using FAD (BLUF) domain-containing proteins encoded in the A. nosocomialis genome, which account for the only "traditional" light sensors present in this microorganism. By focusing on a light-modulated bacterial process such as motility, the temperature dependence of light regulation was studied, as well as the expression pattern and spectroscopic characteristics of the different A. nosocomialis BLUFs. Our results show that the three BLUF-containing proteins encode active photoreceptors, despite only two of them are stable in the light-regulatory temperature range when expressed recombinantly. In vivo, only the A. baumanniis ortholog AnBLUF65 is expressed, which is active in a temperature range from 15 {degrees}C to 37 {degrees}C. In turn, AnBLUF46 is an active photoreceptor between 15 {degrees}C to 32 {degrees}C in vitro, but is not expressed in A. nosocomialis in the conditions tested. Intra-protein interactions were analyzed using 3D models built based on A. baumannis photoreceptor, to support spectroscopic data and profile intra-protein residue interactions. A general scheme is presented on how hydrophobic/aromatic interactions may contribute to the stability of dark/light- adapted states, indicating the importance of these interactions in BLUF photoreceptors.

biochemistry↗