# Chromosome breakage, pairing and replication: impacts on cell fate and function

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $381,250

## Abstract

Project Summary
 This proposal describes investigations in three main areas to understand how the organization of
chromosomes in the nucleus, and their differentiation into heterochromatin and euchromatin, impacts
chromosome breakage and repair, chromosome pairing, and chromosome replication in Drosophila
melanogaster. In the first part, dicentric chromosomes are generated in the male germline, where they typically
break, delivering a chromosome with a broken end to each daughter cell. The influence of structurally distinct
centromeres and the amount of centromeric histone CenpA on the fate of these chromosomes will be examined.
Experiments will be undertaken to understand how cells with a broken chromosome choose their fate, to repair
or to die, and how they choose between different modes of repair. These choices have obvious relevance for
human health. When a cell lives, but fails to repair damage, it may become cancerous. The mode of repair can
determine whether gametes transmit a normal genome, or a genome with deficiencies or other structural variants
or mutations. One particular mode of repair, Break Induced Replication, is known to be mutagenic in yeast, and
has been implicated in chromosome change in humans. Chromosomes repaired by BIR will be examined to
determine the types and frequencies of mutations produced in the germline of a higher eukaryote.
 In the second part of this work, the mechanism of mitotic chromosome pairing will be examined.
Significant progress has been made in identifying genes that promote or inhibit pairing, but how homologous
regions of chromosomes find each other to initiate pairing is still a mystery. This work will test various models for
the initiation of pairing by studying the frequency of site-specific recombination within and between rearranged
chromosomes. This work also has human health relevance, since failures of meiotic pairing can lead to gametes
with chromosomal aneuploidy. Some cancer cells also show inappropriate homologous pairing, implying a
possible connection between these chromosome and cellular states.
 In the third part of the proposed work, the timing of DNA replication in heterochromatin will be examined.
Mutations in genes that encode proteins that affect heterochromatin will be tested to determine their effects on
replication timing. Proper maintenance of heterochromatin is important for genome stability, and disruption of its
normal pattern of replication can lead to altered gene expression, with impacts on cellular function and health.

## Key facts

- **NIH application ID:** 10388397
- **Project number:** 5R35GM136389-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** KENT G GOLIC
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2020-05-20 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388397

## Citation

> US National Institutes of Health, RePORTER application 10388397, Chromosome breakage, pairing and replication: impacts on cell fate and function (5R35GM136389-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10388397. Licensed CC0.

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