# Defining the effect of centromere/kinetochore associations on genome instability

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2022 · $42,498

## Abstract

PROJECT SUMMARY
Somatic copy number alterations (SCNAs) are an established hallmark of cancer and result from errors in the
mechanisms that maintain genome stability. The presence of SCNAs across most cancer types highlights
prevention of SCNAs as a potential strategy to prevent the generation and propagation of cancer. Prevention
of SCNAs requires the maintenance of genome stability, which is dependent on the normal functioning of
centromeres. Centromeres, which are repetitive DNA domains, are the site of assembly of the kinetochore, a
multi-protein complex that couples centromeres with microtubules and regulates chromosome segregation.
Interestingly, the repeat-rich architecture of centromeres makes them prone to genomic rearrangements, with
40-60% of genomic rearrangements in cancer cells occurring at centromeres. Hence, centromeres maintain
genome stability and their own genetic integrity by associating with kinetochore proteins. Cancer initiation and
progression always involve some form of genome instability that leads to SCNA, hence the mechanisms
through which centromere DNA/kinetochore protein interactions contribute to genome stability are an
understudied but critical component of cancer research. The goal of this project is to determine how changes
at the centromere-kinetochore interface impact genome stability, with the long-term goal being to uncover new
mechanisms of genome instability leading to cancer initiation and progression. This proposal is novel because
it is the first to test the mechanistic effect of centromere DNA and associated protein diversity on genome
stability. I hypothesize that centromere variation can influence centromere/kinetochore association and
subsequently impact genome stability. Aim 1 will determine whether CENP-A, a centromere-specific histone
H3 variant, differentially associates with divergent centromere satellite repeats within species, indicating
differential ability of centromere DNA repeats to associate with CENP-A to maintain their stability. Aim 2 will
determine the dependence of kinetochore protein function on centromere sequence compatibility. This will be
done by observing the function of human Shugoshin 1, a kinetochore protein that associates with centromere
DNA to maintain centromeric cohesin during mitosis, with mouse centromere satellite repeats. Together, these
aims will highlight pathways that are dependent on centromere sequence for their function, implicating
centromere-dependent mechanisms to maintain genome stability. My goals for training are (i) to gain an
experimental skill set that will enable me to use a cell culture system to test computationally generated
hypotheses and (ii) to improve my scientific communication skills. These will contribute to my career
development to become an independent academic scientist investigating the role of evolutionary genetic
processes in human cancer incidence and evolution. My graduate program and institution with a successful
training record, ...

## Key facts

- **NIH application ID:** 10385959
- **Project number:** 1F31CA268727-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Uma Arora
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,498
- **Award type:** 1
- **Project period:** 2021-12-16 → 2022-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385959

## Citation

> US National Institutes of Health, RePORTER application 10385959, Defining the effect of centromere/kinetochore associations on genome instability (1F31CA268727-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10385959. Licensed CC0.

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