# Project 1: Chromosome Inheritance

> **NIH NIH P01** · COLD SPRING HARBOR LABORATORY · 2020 · $657,623

## Abstract

PROJECT SUMMARY- PROJECT 1
Cancer cells display uncontrolled inheritance of chromosomes, including errors in DNA replication and mitosis.
These errors cause and propagate mutations and chromosomal abnormalities that further enhance cancer.
Project 1 has been a leader in studying the mechanisms and control of inheritance of the human genome and
has identified many of the key proteins that are involved in DNA synthesis at the replication fork and other
proteins that are involved in the initiation of DNA replication. In the proposed studies, Project 1 will continue
focusing on the mechanism and regulation of the initiation of DNA replication. Project 1 has discovered that
certain initiation proteins are involved in many aspects of the cell division cycle, including centrosome
duplication, centromere function and cytokinesis. Recent results also show that some initiation proteins are
intimately involved in the fundamental decision of whether newly born cells will commit to a new round of cell
division or enter into a period of quiescence. The proposed research will fall into three areas. Specific Aim 1
will focus on the role of the Origin Recognition Complex (ORC) subunit ORC1 and its related protein CDC6 in
regulation of the commitment to cell division by controlling the expression of E2F1-regulated genes, in addition
to the gene encoding Cyclin E, in cooperation with the tumor suppressor protein RB and the histone
methyltransferase SUV39H1. Aim 1 will also focus on how CDC6 cooperates with ORC, RB, SUV39H1 and
Cyclin dependent kinases to promote initiation of DNA replication. Specific Aim 2 will continue to study the role
of the ORC subunits ORC2 and ORC3 at centromeres. ORC2 interacts with the Spindle Assembly Checkpoint
protein BUBR1 only when it is phosphorylated during mitosis and defects in the BUBR1 binding domain of
ORC2 cause the persistence of chromosomes that fail to align at the metaphase plate. Aim 2 will determine
how ORC2 binds to BUBR1 and controls access of BUBR1. How ORC2 and ORC3 are recruited to
centromeres, and the role of ORC3 interaction with the HP1 heterochromatin protein in chromosome
segregation will also be studied. Project 3 will also study E2f1-regulated control of cell proliferation in a subset
of breast and colon epithelial cancers have an acquired dependence of the DEAD-box RNA helicase DDX5.
DDX5 is also required for progression of Acute Myeloid Leukemia (AML). This Aim will investigate how DDX5
becomes essential in some adult cancers and AML, while dispensable in normal epithelial and normal
hematopoietic cells. Both RNA and protein binding partners will be identified, comparing both DDX5-dependent
(DDX5-D) and DDX5-independent (DDX5-I) breast cancer cells. Exploiting the differential dependence on
DDX5, Anti-Sense Oligonucleotides (ASO) will be developed for studying the role of DDX5 in mouse models
for breast cancer and AML.

## Key facts

- **NIH application ID:** 9851819
- **Project number:** 5P01CA013106-48
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** BRUCE W. STILLMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $657,623
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851819

## Citation

> US National Institutes of Health, RePORTER application 9851819, Project 1: Chromosome Inheritance (5P01CA013106-48). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851819. Licensed CC0.

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