# DNA helicases and associated factors in genome stability

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2020 · $377,773

## Abstract

PROJECT SUMMARY
DNA helicases represent one of very few enzyme classes that function in virtually all aspects of DNA replication,
recombination, repair, and telomere maintenance. As such, they are vital to maintaining genome integrity and
are disease linked when mutated. Thus, there is a critical need to comprehensively understand helicase biology
and how these enzymes support genome integrity. Despite many in vivo and in vitro advances in working with
helicases, there is a gap in knowledge connecting mutant alleles of helicase genes to the treatment of patients
in clinics. The objective of my research is to gain mechanistic insight into how DNA helicases function in genome
maintenance and why their dysfunction leads to disease. Toward this goal, we are studying PIF1 and RecQ
family helicases, both because they are evolutionarily conserved in all domains of life (giving us our pick of model
systems to dissect the various aspects of their biology) and because the human PIF1 and RecQ helicases are
oncogenes. Indeed, mutations in the genes encoding these helicases are associated with multiple diseases, as
well as predispositions to cancers and premature aging. Our current work focuses on the roles of RecQ helicases
in DNA inter-strand crosslink (ICL) repair and RecQ and Pif1 helicases in telomere maintenance. The proposed
work will: 1) determine how RecQ4 subfamily helicases and Pso2 family nucleases function in Fanconi anemia-
independent DNA ICL repair, identify other factors involved in this repair pathway, and examine how disease
alleles of RECQL4 perturb its genome maintenance functions at a mechanistic level; 2) define how PIF1 and
RecQ helicases synergistically modulate telomerase activity, determine the impacts of other telomere binding
proteins on the biochemistry of these helicases, and reconstitute the telomerase holoenzyme in vitro; and 3)
determine the regulatory effects of lysine acetylation on PIF1 family helicases in yeast and humans and how this
is linked to genome integrity. To perform this work, we will employ a variety of classic and cutting edge
experimental techniques, from standard in vitro enzymatic assays and model organism genetics to next-
generation sequencing, crosslinking mass spectrometry, and the development of custom click chemistry probes.
Overall, this work will provide fundamental data critical to understanding how PIF1 and RecQ family helicases
aid in the maintenance of genome stability, and it will ultimately lead to therapeutic targets and treatments for
helicase-linked diseases.

## Key facts

- **NIH application ID:** 9984458
- **Project number:** 5R35GM133437-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Matthew Linne Bochman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,773
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984458

## Citation

> US National Institutes of Health, RePORTER application 9984458, DNA helicases and associated factors in genome stability (5R35GM133437-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9984458. Licensed CC0.

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