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problems (reviewed in Ref. 1 ). It has been suggested that NusA may be
involved in a form of TCR that is independent of Mfd and can account for
the mild effect of mfd mutations; 58,59 however, there is as yet no direct
biochemical evidence for TCR in the absence of Mfd . Furthermore, the
biological response (MFD) that reflects TCR and was the basis for the subse-
quent identification of Mfd is absent when the protein is not active. In Bacillus
subtilis , Mfd has been implicated in recombination, 70 and in both B. subtilis 71
and Campylobacter jejuni , 72 it has been reported to have a mutagenic effect. In
addition, Mfd has been reported to release ECs arrested by the bacteriophage
HK022 Nun protein. 73 Until the biochemical bases for these observations are
known, interpreting an Mfd -dependent biological response as TCR without
direct measurements of repair is of questionable validity.
Note added in proof : In contrast to data implicating TCR in the repair of
oxidative lesions, Schalow et al. (J. Bacteriol. 2012;194: 2637-2645) have
reported that neither mfd nor uvrA mutations affect the survival, the rate of
recovery of transcription, or the rate of removal of formamidopyrimidine DNA
glycosylase sensitive sites in the DNA of actively growing E. coli treated with
H 2 O 2 , consistent with the idea that neither TCR nor GGR contribute signifi-
cantly to the repair of oxidative lesions produced by this compound.
In addition, Deaconescue et al. ( Proc Nat Acad Sci USA 2012;
:3353-
3358) recently published studies of the structure of Mfd , providing more details
about the interaction of Mfd with UvrA and the conformational changes the
protein undergoes during its interactions with other components of TCR. Their
data, like those of Manelyte et al. , 39 indicate that Mfd can dissociate a stalled
EC without interacting with UvrA ; they propose that the likely sequence of
events in TCR is the interaction of Mfd with a stalled EC by protein-protein
contacts and the dissociation of the EC prior to the recruitment of UvrA .
109
Acknowledgments
Support for our research on TCR for many years was provided by grants from the National
Cancer Institute, NIH 5R35 CA44349, RO1 CA91456, and RO1 CA90915. Current support is
provided from grant 1RO1 ES0188344 from the National Institute of Environmental Health
Sciences, NIH.
References
1. Hanawalt PC, Spivak G. Transcription-coupled DNA repair: two decades of progress and
surprises. Nat Rev Mol Cell Biol 2008;
:958-70.
2. Witkin EM. Radiation-induced mutations and their repair. Science 1966;
9
:1345-52.
3. Zolan ME, Cortopassi GA, Smith CA, Hanawalt PC. Deficient repair of chemical adducts in
alpha DNA of monkey cells. Cell 1982;
152
:613-9.
28
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