# Polyploidy, Aneuploidy and Genome Stability

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $528,660

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this proposal is to determine the mechanistic basis for mutational processes that drive very rapid
evolution of cancer genomes. One process causing mutation bursts is chromothripsis, massive rearrangement
of one or a few chromosomes occurring within a single cell division. Under this grant, my group established a
general mechanism for chromothripsis. This work was enabled by our development of a novel technical
approach, the ability to combine live cell imaging, same cell isolation, and single cell whole genome sequencing
(Look-Seq). Chromothripsis originates from abnormal structures of the nucleus—micronuclei (MN) or
chromosome bridges. We identified a defect in nuclear envelope assembly on chromatin that lags within the
mitotic spindle. This results in nuclear envelope (NE) fragility and spontaneous NE rupture. Exposure of MN
chromatin to the interphase cytoplasm leads to extensive DNA damage, which is followed by a second wave of
DNA damage upon entry into mitosis. The first two aims of this proposal address the mechanisms leading to
chromosome fragmentation that is the basis for chromothripsis. First, building on preliminary data we will test
the hypothesis that exposure of MN chromatin to the interphase cytoplasm causes DNA damage via an aberrant
pathway of DNA base excision repair. Second, we propose hypothesis driven and unbiased approaches to
identify the mechanism of MN chromosome fragmentation in mitosis. Finally, we address the mechanism of
another poorly understood, common cancer genome catastrophe termed chromoplexy.

## Key facts

- **NIH application ID:** 10366301
- **Project number:** 2R01CA213404-24
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** DAVID S PELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,660
- **Award type:** 2
- **Project period:** 1997-05-30 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366301

## Citation

> US National Institutes of Health, RePORTER application 10366301, Polyploidy, Aneuploidy and Genome Stability (2R01CA213404-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10366301. Licensed CC0.

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