# The DREAM B-Myb-MuvB complex controls sensitivity to DNA replication activators and inhibitors

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2020 · $90,877

## Abstract

Research
our
during
coordination
efficacy.
Summary
response to DNA damage, down-regulation of cell cycle genes contribute to cell cycle arrest. Recently,
lab has uncovered a novel insight into cell cycle gene control t hat prevents mitotic events from occurring
S phase. This insight into how DNA damage response and DNA replication-inhibitors can affect the
between the G1/S and G2/M genes can help to improve our understanding of chemotherapy
The MuvB core complex is a five-protein complex that
In
orchestrates cell cycle-dependent gene
expression through the formation of at least three functionally distinct complexes. In
component
expression
through
expression
G0/G1, MuvB is a
of the DREAM complex ( D P, R B-like, E 2F, a nd M uvB), which maintains quiescence by repressing
of G1/S and G2/M genes. In S phase, MuvB switches from epressing to activating complexes
sequential recruitment of B-Myb and FoxM1. The B-Myb-MuvB (MMB) and complexes initiate
of late cell cycle genes through recognition of the Myb, CHR, and Forkhead DNA binding elements.
r
The ATR-CHK1 pathway plays a central role in the cellular response to DNA damage during S/G2. Our lab
performed a genome-wide CRISPR-Cas9 screen to identify genes that, when lost, confer resistance to CHK1
inhibition. We determined that loss of B-Myb, LIN54, or FoxM1 in two different non-small cell lung cancer
(NSCLC) cell lines A549 and H460 led to a 200-fold resistance to CHK1 inhibition as well as a 5-fold resistance
to ATR inhibition compared to control cells. These observations reveal an unexpected role for the MMB-FoxM1
complex as critical components of the S phase DNA damage response (manuscript in preparation). I explored
the sensitivity of these knockout cells to DNA replication-inhibitors, specifically those used clinically for the
treatment of solid tumors and hematologic malignancies. I observed that the LIN54 and FoxM1 knockout cells
were highly sensitive to treatment with the DNA-damaging
cytosine
where
agent competes with
for incorporation into nascent DNA by the DNA polymerase and results in stalled replication forks,
a potent ATR response and activation of p53. R
gemcitabine. Gemcitabine
ecent work from our lab has shown that p53-mediated
cell cycle arrest is jointly enforced by DREAM and RB repressive complexes in response to doxorubicin,
suggesting that disruption of DREAM-MuvB complexes could disrupt p53-mediated cell cycle arrest to DNA
damage. Thus, altering DREAM/MuvB complex formation and activity could result in a potent p53 apoptotic
response in S phase from an impaired cell cycle-controlled arrest and DNA repair. The
research
activators
standard
approaches
inhibitors
goal of this proposed
is to determine the role of the DREAM B-Myb-MuvB complex in sensitivity to DNA replication
 and inhibitors. Completion of the proposed studies will broaden our mechanistic understanding of
chemotherapy treatments. Long-term this work could lead to clinically relevant therapeutic
for cancer treatment...

## Key facts

- **NIH application ID:** 10136185
- **Project number:** 3R35CA232128-02S1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** James A. DeCaprio
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,877
- **Award type:** 3
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136185

## Citation

> US National Institutes of Health, RePORTER application 10136185, The DREAM B-Myb-MuvB complex controls sensitivity to DNA replication activators and inhibitors (3R35CA232128-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10136185. Licensed CC0.

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