Replication DNA polymerases, genome instability and cancer therapies.

It has been over a decade since the initial identification of exonuclease domain mutations in the genes encoding the catalytic subunits of replication DNA polymerases ϵ and δ ( and ) in tumors from highly mutated endometrial and colorectal cancers. Interest in studying and has increased significantly since then. Prior to those landmark cancer genome sequencing studies, it was well documented that mutations in replication DNA polymerases that reduced their DNA synthesis accuracy, their exonuclease activity or their interactions with other factors could lead to increased mutagenesis, DNA damage and even tumorigenesis in mice.

Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development.

Mutations in the exonuclease domain of are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. ; mice showed accelerated cancer mortality compared to ; mice.

Autoreactivity in naïve human fetal B cells is associated with commensal bacteria recognition.

Restricted V(D)J recombination during fetal development was postulated to limit antibody repertoire breadth and prevent autoimmunity. However, newborn serum contains abundant autoantibodies, suggesting that B cell tolerance during gestation is not yet fully established. To investigate this apparent paradox, we evaluated the reactivities of more than 450 antibodies cloned from single B cells from human fetal liver, bone marrow, and spleen.