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This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2] . MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted. [ABSTRACT FROM AUTHOR]

The article comments on the study "Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis," by J. Ortega and colleagues on proliferating cell nuclear antigen protein (PCNA) phosphorylation. Topics include the inhibition of epidermal growth factor receptor (EGFR) in mismatch repair of DNA, the role of PCNA, and the nuclear transport of ligand-bound EGFR.

Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by "inverting" the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers. [ABSTRACT FROM AUTHOR]

The article presents the discussion on targeting a neoantigen derived from a common TP53 mutation. Topics include proteins encoded by tumor suppressor genes being inactivated through mutation; intracellular protein located within the nucleus reaching for conventional antibody-based therapies; and proteins being degraded into peptides by the proteasome and a fraction of these peptides presented by the human leukocyte antigen (HLA).