Characterization of POLE c.1373A > T p.(Tyr458Phe), causing high cancer risk.

The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of POLE and POLD1, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers.

A new negative feedback mechanism for MAPK pathway inactivation through Srk1 MAPKAP kinase.

The fission yeast mitogen-activated kinase (MAPK) Sty1 is essential for cell survival in response to different environmental insults. In unstimulated cells, Sty1 forms an inactive ternary cytoplasmatic complex with the MAPKK Wis1 and the MAPKAP kinase Srk1. Wis1 phosphorylates and activates Sty1, inducing the nuclear translocation of the complex.

Role of POLE and POLD1 in familial cancer.

Purpose: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study.

Methods: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics).

RNA-Binding Protein Rnc1 Regulates Cell Length at Division and Acute Stress Response in Fission Yeast through Negative Feedback Modulation of the Stress-Activated Mitogen-Activated Protein Kinase Pathway.

RNA-binding proteins (RBPs) play a major role during control of mRNA localization, stability, and translation and are central to most cellular processes. In the fission yeast , the multiple K homology (KH) domain RBP Rnc1 downregulates the activity of the cell integrity pathway (CIP) via stabilization of mRNA, which encodes the Pmp1 phosphatase that inactivates Pmk1, the mitogen-activated protein kinase (MAPK) component of this signaling cascade. However, Rnc1 likely regulates the half-life/stability of additional mRNAs.

Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures.

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.