# Function of the Bloom's syndrome DNA helicase in the maintainance of genome integrity

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $336,893

## Abstract

PROJECT SUMMARY
The RecQ-like DNA helicase BLM is known for its critical role in the response to and repair of DNA-double-
strand breaks in mammalian cells. Disruption of BLM activity causes Bloom’s syndrome, which is characterized
by extreme cancer risk, short stature, and an average life expectancy of 25 years. Cancer susceptibility,
chromosome breakage and other cellular defects are currently explained by the lack of BLM’s activity in the
DNA-damage response and homologous recombination. In this proposal we are testing the hypothesis that
BLM plays critical roles in DNA replication initiation and elongation to maintain chromosome stability
in unperturbed cells. This hypothesis is based on extensive preliminary data, including an unbiased screen of
the mid-S-phase proteome that led to the discovery that chromatin-bound BLM directly interacts with the Mcm6
subunit of chromatin-bound Mcm2-7. Notably, two distinct binding sites in BLM and Mcm6 differentially
regulate complex formation in G1 and S-phase, and disruption of the BLM/Mcm6 interaction in S-phase, but
not in G1, leads to supra-normal DNA replication speed. Aberrant acceleration of DNA replication speed
beyond a safe limit is emerging as a mechanism that causes DNA damage and kills certain types of cancer
cells. Our preliminary findings suggest that the BLM/Mcm6 interaction acts as a novel, negative regulator
of DNA replication in human cells. That cells lacking BLM do not exhibit increased replication speed
suggests that acceleration of replication requires the BLM protein, leading us to hypothesize that BLM needs
to be tethered to Mcm6 to restrict the ATPase/helicase activity of BLM to the immediate vicinity of the
replisome. Together with BLM’s ability to unwind G-quadruplexes (G4s) and their presence throughout the
human genome, including at ~90% of origins of replication, we propose that BLM is recruited by Mcm6 to
unfold DNA structures (i) at replication origins to facilitate the G1/S transition (Aim 1) and (ii) throughout the
genome to regulate replisome progression during unperturbed S-phase (Aim 2). We have isolated a set of
BLM mutants that specifically fail to interact with Mcm6 in G1 or S-phase, or both, to identify the separate
functions of the BLM/Mcm6 interaction in G1 and S-phase and to determine replication-associated mitotic
defects. Further, we will use biophysical approaches and molecular dynamics simulations to determine the
mechanism of G4 unwinding by BLM (Aim 3). Completing these studies will delineate a major new function for
BLM in unperturbed DNA replication, besides its established role in DNA double-strand break repair and
replication fork restart after DNA damage, and determine its mechanism of G4 unwinding. Our findings will
provide a major advance in our understanding of the mechanisms that prevent chromosome instability in
unperturbed cells and improve our understanding of chromosome breakage syndromes and cancer
predisposition.

## Key facts

- **NIH application ID:** 10457409
- **Project number:** 5R01GM139296-03
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Kristina Schmidt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,893
- **Award type:** 5
- **Project period:** 2020-09-04 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457409

## Citation

> US National Institutes of Health, RePORTER application 10457409, Function of the Bloom's syndrome DNA helicase in the maintainance of genome integrity (5R01GM139296-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10457409. Licensed CC0.

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