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Multi-faceted Regulation of Dynamic SUMOylation at ALT Cancer Telomeres

Award Number: R01CA308360
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Multi-faceted Regulation of Dynamic SUMOylation at ALT Cancer Telomeres - Project Summary A key feature of cancer cells is their infinite growth, which depends on their ability to elongate the repetitive sequences at the ends of chromosomes known as telomeres. Cancer cells use either telomerase or the alternative lengthening of telomeres (ALT) pathway to extend telomeres. Unlike telomerase-positive cancers, which can be targeted by several drugs currently in clinical trials, there are no therapeutics specifically designed for ALT cancers due to the lack of suitable targets. ALT cancer cells employ homology-directed repair (HDR) pathways that occur in ALT-telomere-associated PML bodies (APBs). These APBs serve as unique diagnostic markers and potential therapeutic targets for ALT cancer. We and others have shown that APB formation requires establishing a SUMOylation hub at ALT telomeres, where various proteins are modified by small ubiquitin-like modifiers (SUMO). SUMO supports APB formation and plays critical and direct roles in facilitating ALT telomere synthesis. These findings suggest that targeting SUMOylation could be effective in ALT cancer therapy. However, a better understanding of several key questions is needed to specifically target ALT telomere SUMOylation. First, what series of events lead to the creation of a SUMOylation hub at ALT telomeres? Second, how is SUMOylation dynamically regulated to support different steps of DNA repair at ALT telomeres? With our expertise in SUMOylation in DNA repair and ALT cancer, our team is well-equipped to address these questions through an integrated approach, including cutting-edge chemo-optogenetic manipulation combined with live-cell imaging, structure prediction-guided mutagenesis, and biochemistry. Building on our recent discovery that Rad52, an essential repair factor in ALT telomere synthesis, also has a critical role in enriching SUMO at ALT telomeres, we will investigate how Rad52 contributes to forming a SUMOylation hub at ALT telomeres in Aim 1. In Aim 2, we will explore how SUMOylation is reversed at ALT telomeres and how deSUMOylation facilitates the completion of ALT telomere synthesis during the cell cycle. Additionally, we will evaluate the potential of targeting deSUMOylation enzymes for ALT therapy by testing whether inhibiting these enzymes sensitizes ALT cells in existing and patient- derived ALT-positive osteosarcoma cell lines. The results from these aims are expected to reveal insights into the unique features of SUMOylation at ALT telomeres and to improve strategies for targeting the SUMO pathway in ALT cancers such as osteosarcoma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $521,523 )
2026	2026	CARNEGIE-MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cancer Cause and Prevention Research	000	1	7/7/2026	NEW	$521,523
														Subtotal = $521,523

Grand Total All Awards = $521,523

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Multi-faceted Regulation of Dynamic SUMOylation at ALT Cancer Telomeres

Award Number: R01CA308360

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/06/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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