MMR. This repair has to deal with mismatches between the four regular bases, by modified bases, and
especially by nucleotide insertions and deletions arising from erroneous polymerase activity (often in
repetitive mono- or di-nucleotide regions of DNA) and it restores normal Watson–Crick base-pairing. This
subject has become increasingly significant through the discovery that defective MMR is associated with
familial and sporadic gastrointestinal and endometrial cancer and is also common in some acute myeloid
leukaemias that can follow successful chemotherapy for a primary malignancy.
MMR is primarily a DNA excision repair pathway. Its main targets in man are GT, GG, AC and CC and
also O^6 -MeGT and O^6 -MeGC mismatches. Four key human proteins are involved in MMR: hMSH2,
hMSH6, hMLH1 and hPMS2. First, a base-mismatch is recognised by a MutScomplex (a heterodimer of
hMSH6 and hMSH2), which, in binding, recognises errors in the newly-synthesised daughter strand (Figure
8.43b). Some features of this complex have been revealed in two X-ray structures of bacterial MutS com-
plexes. ATP hydrolysis then is linked to conformational changes that are associated with binding of MutL
(a dimer of hMLH1 and hPMS2) and formation of a loop structure. One or more 5→ 3 exonucleases and
helicase then degrade and elongate the daughter strand loop and the gap is repaired by Pol and DNA liga-
tion to seal the nick. Such MMR repair tracts are 10 to 100 times longer than in NER or BER, respectively.
8.11.7 Preferential Repair of Transcriptionally Active DNA
Preferential repairsimply means that the more important parts get fixed first. It has been known for over
30 years that DNA repair is a heterogeneous process. In 1985, work by Phil Hanawalt established that a tran-
scriptionally active gene is repaired preferentially to the genome overall. He introduced the term prefer-
ential repair to describe the phenomenon that is caused by interactions between a stalled pol II transcription
Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 331
Figure 8.43 Mechanisms of DNA repair. (a) Bacterial base excision repair (BER)illustrated for the cis-syn-thymine
photodimer. (i) An endonuclease makes an incision on 5-side of the dimer; (ii) incision of 3-side and
removal of a 12-base oligomer containing the lesion; (iii) gap enlarged by exonuclease; (iv) polymerase
resynthesis; and (v) ligation to complete patch (red line). (b) Human mismatch repair(MMR) illus-
trated for a GT mismatch in a duplex having a nick to identify the daughter strand. (vi) The mismatch
is recognised by the hMutheterodimer; (vii) ATP drives the threading of loops through hMutSand
recruits hMutL; (viii) exonuclease and helicase action degrade the error-containing strand (identified
by a single strand break); and (ix) replication proteins fill the gap which is sealed by DNA ligase I