# Double strand break repair maelstrom: causes, mechanisms and genome destabilizing consequences

> **NIH NIH R35** · UNIVERSITY OF IOWA · 2021 · $377,822

## Abstract

Maintaining genetic stability is of paramount importance for the survival of cells and organisms. Double-strand
DNA breaks (DSBs) are the most lethal DNA lesion threatening genomic stability, and cells have evolved a
variety of mechanisms for their repair. While some of the repair mechanisms are accurate, others are “risky”
and can further destabilize the genome, leading to cancer and other diseases in humans. The molecular
events that draw the intermediates of otherwise accurate repair pathways into a “maelstrom” of destabilizing
DNA repair mechanisms, where these intermediates are then processed through risky DNA repair pathways,
remain unexplored. The goal of our research is to understand how DSB repair is channeled into the deleterious
repair pathways, with particular emphasis on three DSB repair phenomena: 1) break-induced replication (BIR),
an unusual type of long-tract repair DNA synthesis that promotes bursts of genetic instabilities; 2)
microhomology-mediated BIR (MMBIR), a replicative pathway involving multiple template switching events at
positions of microhomologies that yields complex genomic rearrangements; and 3) the transformation of long
single-strand DNA intermediates of DSB repair into “toxic” joint molecules promoting cell death. As a starting
point, we are using our dependable and powerful system in yeast, where a single DSB is initiated by a site-
specific HO endonuclease; we have demonstrated that all three of the repair events of interest can be used to
repair the lesion in this system. The knowledge obtained using this system – the repair mechanisms,
intermediates, participating proteins, and mutation patterns – is used to inform the experimental design of
studies that will evaluate these pathways in other yeast and mammalian systems. Conceptually, the long-term
goals are the same across projects and involve three primary areas of inquiry. First, using sensitive genetic
approaches, proteins and DNA motifs whose presence affect the funneling of the repair intermediates into the
“maelstrom” of destabilizing repair mechanisms will be identified. Second, a combination of in vivo and in vitro
approaches will be used to model and investigate the cell's decision points to understand the circumstances
(structures, kinetics, participating proteins, etc.) that draw intermediates into high-risk and/or toxic repair
pathways. Third, the patterns of mutations and chromosomal rearrangements that result from the deleterious
repair pathways will be evaluated, and computational approaches will be used to apply these findings to
human genome databases. To this end, MMBIRFinder, new software developed from previous research, will
be used to detect complex genetic changes that cannot be found by currently available algorithms. Overall, this
research program will bring improved clarity regarding the mechanisms of DNA repair intermediate processing,
which will uncover factors that influence the regulation of dangerous repair pathways and result...

## Key facts

- **NIH application ID:** 10159282
- **Project number:** 5R35GM127006-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Anna L Malkova
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,822
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159282

## Citation

> US National Institutes of Health, RePORTER application 10159282, Double strand break repair maelstrom: causes, mechanisms and genome destabilizing consequences (5R35GM127006-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159282. Licensed CC0.

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