# DNA ADDUCTS, REPLICATION, MUTATION AND TRANSFORMATION

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1988 · $131,308

## Abstract

In previous studies, we have observed distinct cycle phase susceptibilities
for toxicity and neoplastic transformation in 10T1/2 cells treated with
methylating chemicals.  Although G1 and S phase cells are susceptible to
cytotoxicity (and, apparently, mutation), only S phase cells are markedly
susceptible to neoplastic transformation.  Although the period of maximal
susceptibility for all of these cellular responses is S phase, our
observations suggest that different types of DNA damage and/or different
rates of DNA repair, and different DNA targets are responsible for
different pathological responses.  In previous studies we have that total
alkylations produced in DNA by MNNG do not vary with the cell cycle,
whereas, repair of selected specific adducts varies widely both in rate and
with cycle phase.  We hypothesize that cytotoxicity and mutation are
produced by a relatively common adduct(s) that is (are) repaired slowly
enough so that many lesions introduced during G1 persist into S phase.  We
posit that transformation is caused either by a lesion(s) that is (are)
repaired rapidly so that lesions produced in G1 are repaired virtually
completely before S phase, or by a unique lesion introduced into DNA only
during S phase.  Furthermore, we also hypothesize that both neoplastic
transformation and mutation are related to damage incurred in specific DNA
sites (targets), whereas cell death results from more random damage to
DNA.  The aim of this proposal is to test these hypotheses in synchronized
C3h 10T1/2 cells exposed in vitro to chemicals that introduce methyl or
ethyl groups (MMS, MNNG, EMS, ENNG) into DNA by Sn1 of Sn2 reations,
producing different spectra of adducts.  Quantitation of DNA damage and
repair and of cytotocxicity, mutation, and neoplastic transformation when
populations of 10T1/2 cells are exposed to chemicals at specific points in
the G1 and S phases of the cycle should allow us to corroborate or refute
our hypotheses.

## Key facts

- **NIH application ID:** 3170096
- **Project number:** 5R01CA032036-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **SAM.gov UEI:** D3LHU66KBLD5
- **Principal Investigator:** JOE W GRISHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $131,308
- **Award type:** 5
- **Project period:** 1982-05-01 → 1988-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3170096

## Citation

> US National Institutes of Health, RePORTER application 3170096, DNA ADDUCTS, REPLICATION, MUTATION AND TRANSFORMATION (5R01CA032036-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3170096. Licensed CC0.

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