# Understanding the novel action of PARPi in ALT-dependent tumors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $369,431

## Abstract

PROJECT SUMMARY/ABSTRACT:
Our long term objective is to improve the therapy of tumors that rely on the alternative lengthening
of telomere (ALT) mechanism. Approximately 10% of all tumors, including nearly all lower-grade
astrocytomas, do not express telomerase but rather use a recombination-based ALT mechanism
to extend their telomeric DNA. Because ALT is not used by normal cells, it represents an attractive
therapeutic target.
 Along these lines we recently showed that the telomeres of ALT-dependent cells are uniquely
dependent on PARP1 to suppress fusion of their dysfunctional telomeres, and that this ALT-specific
protection could be reversed by exposure to PARP inhibitors (PARPi), which in turn led to fusion of
telomeric DNA ends, and cell death in vitro and in vivo. This PARPi-induced chromosomal fusion
therefore represents a novel telomere-directed action of PARPi as well as a potential new therapeutic
avenue for ALT-dependent tumors.
 In the course of our studies, however, we noted that exposure of ALT-dependent cells to PARPi
caused not one but two physically distinct forms of chromosomal fusion: chromosome-type fusions
typically noted following TRF2 depletion, and chromatid-type fusions, which are unusual and
indicative of dysregulated cNHEJ. Furthermore, PARPi lethality was specifically associated with
the appearance of the chromatid-type fusions. We don't currently understand how chromatid-type
fusions are triggered by PARPi, or how to enhance their formation. We noted, however, that three
proteins reported to suppress aberrant chromatid-type fusion (MRE11, CYREN, and Apollo) all
localize to ALT telomeres, and as direct or indirect binding partners of PARP1 could be regulated
in a PARP-dependent manner. We also noted that chromatid-type fusions were associated with
aneuploidy and non-reciprocal translocations, suggesting that these fusions might be processed in
a more lethal manner. Finally, we noted that only a sub-set of PARPi induced chromatid-type
fusion, but that this fusion could be enhanced by combined exposure to ATM inhibitors. Based on
these observations we hypothesize that PARPi block the function of telomeric proteins that
normally limit lethal chromatid-type fusion, and that the use of PARPi/ATMi combinations
will maximize chromatid-type fusions and ALT tumor cell killing. This hypothesis will be
examined by 1) determining if PARP1 regulates the proteins that inhibit chromatid-type fusion, 2)
determining why PARPi-induced chromatid-type fusions are associated with the ALT cell-specific
lethality 3) determining how ATMi synergize with PARPi and to identify agents that similarly
synergize with PARPi in ALT-dependent cells.

## Key facts

- **NIH application ID:** 10521105
- **Project number:** 1R01CA265983-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Russell O. Pieper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $369,431
- **Award type:** 1
- **Project period:** 2022-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521105

## Citation

> US National Institutes of Health, RePORTER application 10521105, Understanding the novel action of PARPi in ALT-dependent tumors (1R01CA265983-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10521105. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*