Targeting Mismatch Repair defects: A novel strategy for personalized cancer treatment

A ‘Semi-Protected Oligonucleotide Recombination’ Assay for DNA Mismatch Repairin vivoSuggests Different Modes of Repair for Lagging Strand Mismatches

“…In eukaryotic mismatch repair, 5΄-directed repair does not require a nick to direct excision while 3΄-repair does, and these results may suggest a conservation of mechanism with respect to how repair is coordinated directionally. Use of the SPORE assay in human cells to identify any mechanistic differences in the mismatch repair of, for example, chemotherapeutically-derived DNA damage sites recognized by different MutS homologues versus naturally-occurring replication errors may further help in the identification of new pharmaceutical targets for synthetic lethality (90). …”

Eukaryotic Mismatch Repair in Relation to DNA Replication

“…However, this mismatch is corrected by MMR (18, 36, 96), with an efficiency so high in one study as to lead to the suggestion that recognizing mismatches opposite damaged bases may be more important than correcting undamaged mismatches (18). MMR also corrects mismatches resulting from misincorporation of damaged dNTPs in mammalian cells (see 118 and references therein), a fact that has implications for chemotherapy (4, 26). …”

“…MMR proteins also modulate cellular responses to environmental stress, prevent recombination between diverged sequences, modulate development of the immune system, influence the stability of trinucleotide repeat sequences associated with degenerative diseases, and participate in meiosis. All of these subjects continue to garner widespread interest, as evidenced by the large number of review articles on the functions of MMR proteins published this year alone (4, 12, 20, 24, 33, 41, 43, 44, 53, 59, 72, 74–77, 86, 108, 109, 113a, 127, 150). The broad range of topics covered in these reviews allows us to focus this review on relationships between MMR and nuclear DNA replication.…”

Aberrant DNA repair as a potential contributor for the clonal evolution in subsets of anaplastic thyroid carcinomas arising through dedifferentiation: implications for future therapeutic algorithms?

“…Even though partial responses have been noted, exceedingly few patients survive once the tumor spreads to distant sites [13,14] . The notion that a proportion of ATCs exhibit MMR deficiency should therefore not be overlooked, as MMR deficient tumors could mandate specific therapeutic considerations, and as the hypermutability in turn might give rise to additional targetable mutations [44] . Especially the promising value of immune checkpoint inhibitors in subsets of ATCs should be evaluated against the MMR status of these tumors, as the hypermutability in MMR deficient ATCs in theory would generate a massive overrepresentation of "non-self " tumoral antigens, in turn priming the patient's immune response.…”