Mechanisms in E. coli and Human Mismatch Repair (Nobel Lecture)

Abstract

DNA molecules are not completely stable, they are subject to chemical or photochemical damage and errors that occur during DNA replication resulting in mismatched base pairs. Through mechanistic studies Paul Modrich showed how replication errors are corrected by strand‐directed mismatch repair in Escherichia coli and human cells.

Oxidative DNA damage & repair: An introduction

“…Tomas Lindahl, Paul Modrich and Aziz Sancar are the 2015 Nobel Prize Laureates in Chemistry [1–4] who were honored for their pioneering and seminal contributions to the delineation of biochemical mechanisms of several DNA repair pathways including base excision repair (BER) [5–10], mismatch repair (MMR) [11–13], nucleotide excision repair (NER) and enzymatic photoreversal [14–16], 21 years after “DNA repair enzyme” was recognized by the Science magazine as the molecule of the year [17]. …”

Clamping down on copy errors

“…Together, these observations might have solved the long-standing mystery of how the mismatch and excision sites interact, superseding previous models in which the DNA is looped through the MutS clamp or in which the clamp moves in a targeted manner along the duplex 1,8 . The model that emerges from these data suggests that MutS acts as a guiding clamp, sending out scouting clamps to search for hemi-methylated GATC sequences in a highly energy-efficient manner (Fig.…”

“…However, this is not an invention of the modern world; nature has been using DNA spellcheckers for millions of years to avoid genetic errors that arise during DNA replication, which it corrects through a process called mismatch repair. In the bacterium Escherichia coli , repair requires communication between enzymes across long stretches of DNA, and how this occurs has been hotly debated for decades 1–3 . On page 583, Liu et al 4 help to solve this mystery by using state-of-the-art techniques to analyse mismatch repair at the single-molecule level.…”

“…In 2015, Paul Modrich received the Nobel Prize in Chemistry for his seminal contributions to our understanding of mismatch repair 1 . However, many aspects of the process remain unresolved.…”

“…One is that mismatch repair in eukaryotic cells (those that have a nucleus) involves more-complex protein– protein and protein–DNA interactions that have yet to be fully described. For instance, the eukaryotic equivalent of MutL has endonuclease activity, and eukaryotes use different mechanisms for excision depending on whether the break point is 3′ or 5′ of the mismatch 1,3 . Given this complexity, a better understanding of eukaryotic mismatch repair will surely present new mechanistic surprises.…”