# Role of p21 in the toxicity of MC and DMC DNA Interstrand Crosslinks

> **NIH NIH SC3** · JOHN JAY COLLEGE OF CRIMINAL JUSTICE · 2021 · $120,192

## Abstract

Abstract
The overarching goal of this proposal is to investigate the relationship between the structure of
stereoisomeric DNA Interstrand Crosslinks (ICLs) formed by Mitomycin C and
Decarbamoylmitomycin C and the molecular mechanisms of these drugs. Mitomycin C (MC) is
an anticancer drug currently used to treat stomach, anal and lung cancers. The stereochemical
configuration at C1’’ of MC major ICL is R (α ICL). In contrast, Decarbamoylmitomycin C (DMC),
a derivative of MC lacking the O10 carbamoyl group, generates the S stereoisomeric ICL (β
ICL). The scientific premise of the proposed research is that ICLs constitute the molecular basis
for the cytotoxic effects of mitomycins. The central hypothesis is that differences in the local
DNA structures of the α and β-ICLs are responsible for the distinct biochemical responses
triggered by MC and DMC. In particular, contrary to MC, the DNA-adducts generated by DMC
treatment (-ICL) rapidly activate a p53-independent cell death pathway. Thus, the study MC-
DMC provides an ideal model for identifying structural features determining the cell signaling
outcome in the presence or the absence of a functioning p53 pathway.
The significance of this project lies in determining the structure-activity relationship for
stereoisomeric DNA crosslink adducts. In addition, the proposed research will establish how the
α and β-ICLs behave as biological signals to different cell death pathways. The key innovation
of this project is to generate stereoisomeric ICLs on a scale which will allow the study of
biochemical responses using our newly developed biomimetic method. Finally, since p53 tumor
suppressor is frequently mutated in human cancers, the need to identify drugs and pathways
that induce cell death or cell cycle arrest independently of p53 deserves substantial attention.
In order to correlate MC and DMC-adducts structures with the toxicity of the α-ICL and β-ICL,
the following three aims will be pursued: 1) Synthesis of MC and DMC DNA adducts. 2)
Determination of p53-dependent and independent MC/DMC DNA adducts response
mechanisms using proteomics. 3) Determination of the molecular signaling pathway involved
the in G2/M cell cycle arrest triggered by MC/DMC DNA-adducts.
Our study will reveal molecular and cellular networks up or downregulated by MC/DMC and the
α/β-ICLs in p53-dependent and p53-independent cell lines. The proposed work will therefore
identify novel critical molecular therapeutic targets of MC and DMC.

## Key facts

- **NIH application ID:** 10149334
- **Project number:** 5SC3GM105460-07
- **Recipient organization:** JOHN JAY COLLEGE OF CRIMINAL JUSTICE
- **Principal Investigator:** Elise Champeil
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,192
- **Award type:** 5
- **Project period:** 2014-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149334

## Citation

> US National Institutes of Health, RePORTER application 10149334, Role of p21 in the toxicity of MC and DMC DNA Interstrand Crosslinks (5SC3GM105460-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149334. Licensed CC0.

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