# The DNA damage response of fast-cycling erythroblasts

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $598,042

## Abstract

Project Summary Erythropoiesis, or the process of red cell formation, is continuous throughout life. Its
study helps elucidate erythroid disorders, most notably anemia, which accounts for 8.8% of all disability
globally. It is also an accessible model for studying fundamental questions in developmental biology. This
proposal is based on recent finding that a key erythroid cell fate decision is associated with dramatic
shortening of S phase. Cell fate decisions in some other developmental systems are similarly associated with a
faster S phase. A faster S phase might be accomplished at the cost of genomic instability, as in oncogene-
induced replicative stress. However, studies of the relationships between a physiologically faster S phase and
the DNA damage response in normal development are lacking. This project’s goal is to determine whether the
unusually fast S phase of the erythroid developmental switch entails altered DNA replication fidelity and/or
alterations in the DNA damage response.
Early erythroid progenitors, termed ‘colony-forming-unit-erythroid’ (CFU-e), undergo several self-renewal cell
divisions before transitioning into Erythroid Terminal Differentiation (ETD), where they begin to express red cell
genes. The transition from self-renewing CFU-e progenitors to maturing ETD erythroblasts is a rapid
transcriptional switch that is synchronized with, and dependent on, a single cell cycle S phase. Strikingly, the
S-phase of the CFU-e/ETD switch is of uniquely short duration, lasting only 4 hr, compared with 7 hr in
preceding CFU-e cycles, as a result of a global, 50% increase in the speed of replication forks. These changes
in S phase speed are required for the CFU-e/ETD switch; the slower S phase of CFU-e progenitors promotes
their self-renewal, while the fast S phase of early ETD promotes erythroid gene induction. It might be expected
that the fast S phase of early ETD erythroblasts would exact a ‘cost’ of increased replication fork stalling events
(‘replication stress’) and increased genomic instability. our experimental AIMS test two opposing but not
necessarily mutually exclusive hypotheses:
 Hypothesis 1: The faster S phase of early ETD is achieved at a cost of lower quality replication.
 Hypothesis 2: The faster S phase of early ETD reflects “supercharged” replication-coupled DNA repair.
AIM 1 will analyze the quality of DNA replication in fast-cycling early ETD erythroblasts. AIM 2 will determine
how the DNA damage response of fast-cycling ETD erythroblasts differs from that of their slower-cycling CFU-
e precursors. AIM 3 will determine whether the faster S phase and the altered DNA damage response of early
ETD are genetically separable.

## Key facts

- **NIH application ID:** 10317904
- **Project number:** 1R01DK130498-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Ralph Scully
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $598,042
- **Award type:** 1
- **Project period:** 2021-08-25 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317904

## Citation

> US National Institutes of Health, RePORTER application 10317904, The DNA damage response of fast-cycling erythroblasts (1R01DK130498-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10317904. Licensed CC0.

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