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Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions

Award Number: R01CA237153
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions - Tumor cells make mutations, creating genetic variants that adapt to stressful environments. The majority of cancer driver mutations may be caused by replication errors, but the sources and mechanisms of such replication errors in human tumors are poorly understood. This critical gap in knowledge hinders our ability to effectively manage cancer. The human genome is characterized by DNA sequence complexity and high repetitive DNA content, but we lack detailed mechanisms as to how this complex genome is replicated, limiting our understanding of the endogenous processes that promote cancer development. DNA polymerases encounter many Difficult-To-Replicate Sequences, or DiToRS, within repetitive regions that cause replication fork stalling. If not navigated efficiently, DiToRS lead to double strand breaks and genome instability. Our long-term goals are to illuminate mechanisms of human genome replication and expand knowledge of replication errors in tumor evolution. This project will discover how human cells carry out essential synthesis of DiToRS genome-wide, and the genetic consequences of incomplete DiToRS replication. Our established interdisciplinary team has unique expertise in studying DiToRS regions of the human genome, and has made important mechanistic advances towards understanding DiToRS replication. Our recent studies implicate DNA polymerases eta (Pol η) and kappa (κ) as being essential for this process, and advance a new paradigm in which Pols η and κ have adopted critical functions for complex genome replication. Because these polymerases have low fidelity, we hypothesize that by requiring cells to engage Pols η/κ in DiToRS replication, replication stress increases replication errors in tumor cells. To test this innovative hypothesis, we will use human cell models and a physiologic source of replication stress linked to oncogene activation: dNTP substrate depletion. Aim 1 will study DNA polymerase biochemistry and identify key replication proteins required for DiToRS replication. Aim 2 will investigate the critical Pol η functions required to promote tumor cell survival in the presence of replication stress, and the impact of Pol η on ATR/Chk1 inhibitor targeted therapies. Aim 3 will measure mutations arising in non-tumorigenic and tumorigenic cells under stress, and develop new computational tools to interrogate cancer genomes for replication errors. Our mechanistic studies will provide key insights into the mechanisms by which oncogene activation results in replication errors that drive tumorigenesis, and reveal new biomarkers of tumor progression. Insights into mutational mechanisms gained from this project can be leveraged in precision oncology approaches to cancer therapy.


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: 2025 ( Subtotal = $0 )
2025	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	5	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $547,143 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	5	3/6/2023	NON-COMPETING CONTINUATION	$547,143
														Subtotal = $547,143

Issue Date FY: 2022 ( Subtotal = $492,572 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	001	4	5/3/2022	NON-COMPETING CONTINUATION	$40,211
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	4	3/17/2022	NON-COMPETING CONTINUATION	$452,361
														Subtotal = $492,572

Issue Date FY: 2021 ( Subtotal = $537,971 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	3	3/10/2021	NON-COMPETING CONTINUATION	$537,971
														Subtotal = $537,971

Issue Date FY: 2020 ( Subtotal = $502,632 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	2	3/27/2020	NON-COMPETING CONTINUATION	$502,632
														Subtotal = $502,632

Issue Date FY: 2019 ( Subtotal = $518,614 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Cause and Prevention Research	000	1	3/22/2019	NEW	$518,614
														Subtotal = $518,614

Grand Total All Awards = $2,598,932

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Pro-tumorigenic functions of human DNA polymerases eta and kappa during genome duplication under physiological replication stress conditions

Award Number: R01CA237153

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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