# The mechanism of DNA damage and chromothripsis from chromosome segregation errors

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2020 · $177,120

## Abstract

Project Summary/Abstract
Research: Tumorigenesis and resistance to therapy are generally believed to arise through
gradual, multigenerational accrual of mutations. However, recent cancer genome sequencing
suggests that many cancers may accumulate large number of mutations rapidly, perhaps during
the course of a single cell cycle. The most dramatic example of such rapid genome evolution is
chromothripsis, a new mutational process with massive chromosome rearrangements and a
unique pattern DNA copy number that is curiously restricted to one or a few chromosomes.
The mechanism(s) leading to chromothripsis have been unclear, but our group previously
suggested that it could result from the physical isolation of chromosomes in abnormal nuclear
structures called micronuclei. To test this hypothesis, I developed a procedure to combine live-
cell imaging with single-cell whole genome sequencing. This has enabled me, with my
collaborators, to recapitulate chromothripsis in the laboratory and demonstrate that it can occur
via chromosome fragmentation in micronuclei.
 This experimental system now positions me to study the mechanism of chromothripsis in
detail. I will also test my hypotheses that chromothripsis triggers a downstream cascade of
genome instability and drives tumor formation through generation of double minute
chromosomes, and that chromothriptic-like DNA damage may be an important facet of the
tumor killing action of taxanes. Together, these experiments and the new hypotheses being
tested will advance our understanding of the ways by which chromosome segregation errors
shape cancer genomes, leading to development of novel therapeutic strategies.
Candidate Career Goals: My long-term career objective is to obtain a tenure-track position as
a physician-scientist in a radiation oncology department. The K08 award will provide the
advanced training necessary to achieve this goal. This research proposal is part of a structured
plan with scientific, technical, clinical, and career development components.
Environment: DFCI and Harvard University are internationally recognized research programs
with a number of expert researchers in the areas of cancer cell biology and genomics.
Furthermore, DFCI Department of Radiation Oncology has a distinguished record of training
successful physician-scientists. In order to achieve my goals, I will be mentored by two
outstanding scientists, Dr. David Pellman and Dr. Matthew Meyerson. I have also assembled an
excellent advisory committee, consisting of Dr. Alan D’Andrea, Dr. Tim Mitchison, Dr. Gad Getz
and Dr. Harvey Mamon.

## Key facts

- **NIH application ID:** 9938444
- **Project number:** 5K08CA208008-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Alexander Spektor
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $177,120
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938444

## Citation

> US National Institutes of Health, RePORTER application 9938444, The mechanism of DNA damage and chromothripsis from chromosome segregation errors (5K08CA208008-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938444. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*