# DNA MISMATCH REPAIR IN TRANSFORMATION AND MUTAGENESIS

> **NIH NIH R01** · ASSOCIATED UNIV-BROOKHAVEN NATL LAB · 1992 · $287,662

## Abstract

The major goals of this project are to determine the molecular
mechanisms of heteroduplex DNA base mismatch correction in Streptococcus
pneumoniae and to assess the presence of related systems of generalized
mismatch repair in other organisms.  In S. pneumonia such repair occurs
after DNA-mediated chromosomal transformation and after potentially
mutagenic base substitution in DNA replication.  Chromosomal mutations
called hex block action of the repair system.  Two unlinked genes, hexA
and hexB, encode proteins implicated in the repair process.  The genes
have been cloned and their sequences determined.  In addition to
recognizing a mismatch, which can be an abnormal base pair or a short
insertion/deletion, the system targets the strand to be corrected on the
basis, apparently, of single-strand breaks bracketing the mismatch.
These breaks can be a distance of kilobase or more from the mismatch.
One aim is to ascertain whether the breaks in nascent DNA giving Okazaki
fragments are responsible for targeting, and how these breaks, which
appear to be present in the leading as well as the lagging strand being
synthesized, are made.  The possible role of the DNA glycosylases and
AP-endonucleases in causing breaks in the leading strand will be
investigated.  During repair, a target strand segment containing the
mismatch is apparently destroyed.  The role of a pneumococcal DNA
polymerase, which has been cloned, in restoring the DNA strand within
the resulting gap will be tested.  The HexA protein will be purified,
with the help of an antibody directed to it, and the protein will be
characterized with respect to its binding to ATP and to DNA mismatches.
HexB will also be purified.  A possible requirement for ATP hydrolysis
by a complex of HexA and HexB scanning the DNA target for strand breaks
and mismatches will be investigated.  The anti-HexA antibody will be
used to detect cross-reacting proteins in human cell extracts.
Preliminary results indicate such a cross-reacting protein.  This
protein will be isolated and compared to HexA and to a possibly
homologous protein encoded by a gene adjacent to dhfr.  A human protein
homologous to HexB will be similarly sought, and cDNAs encoding both
homologs will be obtained.  They will be used to assess the role of
mismatch repair in  preventing the accumulation of mutations that cause
ageing and to test whether a genetic defect in the system results in the
progeric disease of Werner's Syndrome.

## Key facts

- **NIH application ID:** 3125904
- **Project number:** 2R01AI014885-15
- **Recipient organization:** ASSOCIATED UNIV-BROOKHAVEN NATL LAB
- **Principal Investigator:** SANFORD A LACKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $287,662
- **Award type:** 2
- **Project period:** 1978-04-01 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3125904

## Citation

> US National Institutes of Health, RePORTER application 3125904, DNA MISMATCH REPAIR IN TRANSFORMATION AND MUTAGENESIS (2R01AI014885-15). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3125904. Licensed CC0.

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